Phenylazole compounds, production process and antioxidants

ABSTRACT

The present invention is directed to compounds represented by the formula (1): 
     B-D-Z (1), wherein B represent the following formula (B-1), 
     
       
         
         
             
             
         
       
     
     A represents an optionally substituted imidazole or pyrazole group; 
     
       
         
         
             
             
         
       
     
     E represents the following formula (1a):
 
X represents an oxygen atom, the formula: SOu, or the formula: N—R 9 ;
 
Y represents a carbon atom or a nitrogen atom;
 
D represents an oxygen atom, a sulfur atom or the formula (1a);
 
Z represents (a chroman-2-yl group, a chroman-4-yl group, a 2,3-dihydrobenzofuran-2-yl group, a 2,3-dihydrobenzofuran-3-yl group, etc.) which is substituted with NHR 10  or OR 11 )] or pharmaceutically acceptable salts thereof, and to antioxidants, therapeutic agents for kidney diseases or cerebrovascular disorder, and retinal oxidative damage inhibitors, which include the compounds as the active ingredient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a Divisional Application of U.S. patent application Ser. No.10/566,820, filed Jan. 30, 2006, which is a U.S. National PhaseApplication under 35 U.S.C. 371 of International Patent Application No.PCT/JP2004/011297, filed Jul. 30, 2004 and which claims priority under35 U.S.C. §119 to Japanese Patent Application Nos. 2003-285421 filedAug. 1, 2003, 2003-291881 filed Aug. 11, 2003, 2003-298443 filed Aug.22, 2003, 2004-022958 filed Jan. 30, 2004, 2004-023903 filed Jan. 30,2004 and 2004-023971 filed Jan. 30, 2004, all of which are incorporatedby reference herein. The International Application was published inJapanese on Feb. 10, 2005 as WO 2005/012293 A1 under PCT Article 21(2).

TECHNICAL FIELD

The present invention relates to novel phenylazole compounds, aproduction process thereof, antioxidants containing the compounds as anactive ingredient, and retinal oxidative damage inhibitors, lipoxygenaseinhibitors, 20-HETE production inhibitors, and therapeutic agents forkidney diseases, cerebrovascular or circulatory diseases and cerebralinfarction using the antioxidants.

BACKGROUND ART

It has recently become apparent that the production of lipidperoxidation in the living body and the radical reaction accompanyingthe production of lipid peroxidation exert various adverse influences onthe living body via membrane damage and cell damage. Therefore, it hasbeen made various attempts of applying antioxidants and lipidperoxidation production inhibitors to drugs, and various kinds ofstudies on antioxidants have been made. As the antioxidants, forexample, pharmaceutical compositions containing a specific quinonederivative used for treatment and prophylaxis of endotoxin shockascribable to inflammation or infection; hydroxamic acid derivativeshaving a cell proliferation inhibitory action and a neovascularizationinhibitory action used for treatment and prophylaxis of autoimmunediseases; and 2,3-dihydrobenzofuran derivatives which are useful asantioxidizing agents and radical scavengers (for example, PatentDocument 1) are known. Also, imidazole-based compounds having ananti-hyperlipidemia action, which are useful for treatment andprophylaxis of arteriosclerosis (for example, Patent Document 2); andbenzothiazinecarboxamide which has an anti-arthritis activity and isrepresented by the following formula (for example, Patent Document 3)are known.

Furthermore, there are carbonylaminophenylimidazole derivatives (referto Patent Document 4); aminodihydrobenzofuran derivatives having a lipidperoxidation production inhibitory action which is useful as apreventive or therapeutic agent for various diseases such asarteriosclerosis, hepatopathy and cerebrovascular disorder (PatentDocument 5); antihyperlipidemic agents containing a phenylazole compound(Patent Document 6); dihydrobenzofuran derivatives which significantlyameliorate damage on lipid, protein, carbohydrate and DNA caused as aresult of oxidative stress which arises when an antioxidative defensesystem is insufficient (Patent Document 7); and optically activeaminodihydrobenzofuran derivatives which are useful for amelioration,treatment and prophylaxis of brain functional disorder accompanyingrebral apoplexy and head injury (Patent Document 8).

Regardless of large energy need, since supply of energy depends on bloodcirculation, brain is drastically weak against ischemia. When cerebralblood flow stops by various reasons, resulting in cerebral ischemia,active oxygen species are generated due to mitochondria disorder and anincrease in calcium content in nerve cells. Also it is known that oxygenradicals are explosively generated on reopening of blood stream afterischemia. It is considered that these active oxygen species finallyexerts an action on lipid, protein and nucleic acid and oxidize them,thereby causing cell death. Antioxidants are used for treatment of thesedisease states, and edaravone is permitted as a brain protective agentand used in Japan.

As lipoxygenase (LO) which causes the addition of oxygen to anunsaturated fatty acid typified by arachidonic acid, for example, 5-LO,8-LO, 12-LO and 15-LO are known according to the site to which oxygen isadded. Among these, 5-LO is a primary enzyme which synthesizesleukotriene as a strong inflammation mediator. Lukotrienes is involvedin various inflammatory diseases such as asthma, rheumatic arthritis,inflammatory colitis and psoriasis and control thereof is useful fortreatment of these diseases. It is known that 12-LO and 15-LO react withlinoleic acid, cholesterol ester, phospholipids and low densitylipoprotein (LDL), in addition to arachidonic acid, and causes theaddition of oxygen to the unsaturated fatty acid. It is known thatmacrophage infinitely incorporate oxidation-modified LDL via a scavengerreceptor to form foam cells, which is a first step of formation ofarteriosclerotic focus It is also apparent that 12-LO and 15-LO areexpressed in a high level in the macrophage and is essential as atrigger of oxidative modification of LDL. Control of them is useful fortreatment of various diseases caused by arteriosclerosis.

When arachidonic acid as a precursor of fatty acid is separated fromphospholipids of a cellular membrane, it is converted into 20-HETE by a20-hydroxyeicosatetraenoic acid (HETE) synthase. It is known that20-HETE contracts or extends microvasculature or causes cellproliferation in main organs such as kidney and brain blood vessel. Itis suggested that it is involved in an important physiological effect inthe living body and has a close relation with disease states of kidneydiseases, cerebrovascular diseases and circulatory diseases.Furthermore, it is reported that a phenylazole derivative has aninhibitory action of the 20-HETE synthase.

It is considered that, regarding most ophthalmic diseases which arefrequently caused by aging such as cataract or macular degeneration,oxidative stress involved in free radicals and active oxygen is one ofonset factors. It is known that the retina is a tissue which is likelyto be influenced by aging, together with crystalline lens. The retina islikely to be influenced by various free radicals because it contains alarge amount of a higher unsaturated fatty acid and a nutrient issupplied from both retinal vessel and choriocapillaries, and alsoconsumes a large amount of oxygen. For example, light such as sunlightsupplied throughout one's life is a typical one of oxidative stress tothe retina. Visible light and infrared light account for almost all ofsunlight which arrives at the ground, and several percents ofultraviolet light contained therein strongly interacts with the livingbody as compared with visible light and infrared light and thus itdrastically exerts an adverse influence on health. Ultraviolet light isclassified into UV-A (320 to 400 nm), UV-B (280 to 320 nm) and UV-C (190to 280 nm) according to a difference in wavelength, and the action andintensity to the living body vary. It has been considered thatultraviolet light having a wavelength of 290 nm or less havingparticularly strong cytotoxicity is absorbed by the ozone layer ofstratosphere and hardly arrives at the ground. However, it is consideredthat the appearance of ozone hole, which is considered to be caused byenvironmental disruption, recently increases the dose of ultravioletlight which arrives at the earth and also dermatopathy and cutaneouscancer involved in ultraviolet light increase in the south hemisphere,and thus retinopathy may significantly increase by the influence of UV-Awhich arrives at the retina.

Age-related macular degeneration among ophthalmic diseases isretinopathy which may frequently cause ablepsia, and it is consideredthat ten million people develop slight symptoms and 450,000 or more aresuffering from visual deficit caused by this disease in the States. Alsoin Japan in which the aging society has already been establishedrapidly, there is a fear of an increase in this disease. A mechanism ofthe onset of macular degeneration is unclear. However, it is consideredthat progression of this lesion is involved in the peroxidation reactiondue to light absorption at the retina. Also it is considered that theappearance of a lipofuscin-like fluorescent material referred to asdrusen is recognized at the prophase of the onset and also lipofuscin isproduced by bonding an aldehyde as a secondary decomposition product oflipid peroxidation with a protein, and thus the lipid peroxidationreaction due to ultraviolet light or visible light at the retina caninduce this retinopathy.

A therapeutic agent for retinal diseases containing a specificdihydrofuran derivative, which is useful for prophylaxis and treatmentof retinal diseases due to an antioxidation action, and an agent forchange in visual acuity and retina, including macular degeneration ofthe retina, which contains propionyl L-carnitine or pharmaceuticallyacceptable salts thereof and carotenoid, are known.

Patent Document 1: Japanese Unexamined Patent Application, FirstPublication No. Hei 2-121975

Patent Document 2: Pamphlet of International Publication No. 95/29163Patent Document 3: Specification of German Patent Publication DE3,407,505

Patent Document 4: Japanese Unexamined Patent Application, FirstPublication No. Sho 55-69567Patent Document 5: Japanese Unexamined Patent Application, FirstPublication No. Hei 5-140142Patent Document 6: Pamphlet of International Publication No. WO00/006550Patent Document 7: Pamphlet of International Publication No. WO96/28437Patent Document 8: Japanese Unexamined Patent Application, FirstPublication No. Hei 6-228136

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide antioxidants which areuseful for treatment of ischemic organopathies such as arteriosclerosis,myocardial infarction and cerebral infarction, or treatment of diseasessuch as kidney diseases due to oxidative cell damage, and to provideretinal oxidative damage inhibitors which inhibit retinopathy due tooxidation, particularly photooxidation, lipoxygenase inhibitors, 20-HETEsynthase inhibitors, therapeutic agents for kidney diseases,cerebrovascular or circulatory diseases and cerebral infarction.

The inventors of the present invention have intensively studied so as toachieve the object described above and found that a conventionalantioxidant has insufficient potency because the agent does not arriveat the target site or activity is lost before it arrives at the targetsite, and also they have intensively studied for the purpose ofdeveloping an antioxidant which is more excellent in organ migrationproperties and easily passes a blood brain barrier or a blood retinabarrier. Consequently, compounds represented by the formula (1) haveattained the expected object. Furthermore, they have found that thecompounds have excellent in vivo antioxidation action regardless of anadministration path, and the present invention has been completed.

Furthermore, the inventors of the present invention have studied aboutan influence on the retina by irradiating rat eyes with UV-A at a fixeddose. At the prophase of the onset of retinal diseases such as maculardegeneration, which may frequently cause ablepsia, a lipofuscin-likefluorescent material from a product of the reaction of a lipidperoxidation-derived aldehyde and protein is frequently detected. Anincrease in protein of the protein at about 66 kDa, which is wellproportional to a change in retinal tissue of eyes irradiated with UV-A,is recognized and instrumental analysis and the results of study usingalbumine-free rat reveal that this protein is an albumin-like substance.In vitro autoxidation reaction of the retinal tissue, a significantincrease in the lipofuscin-like fluorescent material is recognized byallowing albumin to coexist. Therefore, an abnormal increase in apartial protein in the retinal tissue as a result of irradiation withUV-A has a relation with an increase in the fluorescent material at theretina, and may cause retinopathy. Heretofore, the inventors of thepresent invention have studied about retinopathy inhibitors consideringa change in a retinal protein as a first biochemical indicator. It hasbeen found that, in the process, the compounds having a strongantioxidation ability of the present invention are migrated to theretina within a short time by oral administration and thus remarkablyinhibit an increase in 66 kDa protein due to spot irradiation with UV-A.Consequently, it has been found that the compounds of the presentinvention are effective to retinopathy due to oxidation and areparticularly effective to relieve progression and symptoms ofage-related macular degeneration of the retina which increases withaging. The present invention has been completed based on this finding.

First, the present invention is directed to a compound represented bythe formula (1):

B-D-Z  (1)

[wherein B represents the following formula (B-1), (B-2) or (B-3):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4), or may represent ahydrogen atom or R₁ when B is (B-3):

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, a C₁₋₆ alkoxy group which may besubstituted with G1, a C₁₋₆ alkylsulfonyl group which may be substitutedwith G1, or a halogen atom; R₆ represents a hydrogen atom, a C₁₋₆ alkylgroup which may be substituted with G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, a benzoyl group which may be substitutedwith G1, or a tetrahydropyranyl group;

G1 represents a cyano group, a formyl group, a hydroxyl group, a C₁₋₆alkoxy group, an amino group, a monomethylamino group, a dimethylaminogroup or a halogen atom,

s represents 0 or an integer of 1 to 3,

t represents 0 or an integer of 1 or 2, and

R₄(s) or R₅(s) may be the same or different when s or t is 2 or more);

R₁ represents a halogen atom, a nitro group, a cyano group, a hydroxylgroup, a C₁₋₆ alkyl group which may be substituted with G2, a C₁₋₆alkoxy group which may be substituted with G2, a C₁₋₆ alkylthio groupwhich may be substituted with G2, a C₁₋₆ alkylcarbonyl group which maybe substituted with G2, an amino group (which may be substituted withone or two C₁₋₆ alkyl groups), a benzoyl group which may be substitutedwith G2, or a benzyl group which may be substituted with G2;

R₂ represents a C₁₋₆ alkyl group which may be substituted with G2;

R₃ represents a hydrogen atom, a C₁₋₆ alkyl group which may besubstituted with G2, a C₁₋₆ alkylcarbonyl group which may be substitutedwith G2, a benzoyl group which may be substituted with G2, or a benzylgroup which may be substituted with G2;

G2 represents a cyano group, a formyl group, a hydroxyl group, a C₁₋₆alkoxy group, a C₁₋₆ alkoxycarbonyl group, a nitro group, an aminogroup, a monomethylamino group, a dimethylamino group or a halogen atom;

m represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when m is 2 or more;

n represents 0 or an integer of 1 to 10, and R₂(s) may be the same ordifferent when n is 2 or more;

o represents an integer of 1 or 2;

p represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when p is 2 or more;

q and r each independently represents an integer of 1 or 2;

in the formula (B-1), the dotted line represents a single bond or adouble bond and does not simultaneously represent a double bond;

Y represents a carbon atom or a nitrogen atom, which may have asubstituent or a multiple bond that satisfies a valence;

E represents an oxygen atom, a sulfur atom or the following formula (1a)when Y represents a carbon atom;

(wherein R₆₀ represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, ora benzoyl group (which may be substituted with a nitro group, a halogenatom, a hydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group); R₇and R₈ each independently represents a hydrogen atom, a cyano group, ahydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆ alkenyloxy group, aC₂₋₆ alkynyloxy group, a C₁₋₆ acyloxy group, a C₃₋₆ cycloalkyl groupwhich may be substituted with G2, or a phenyl group which may besubstituted with G2;

j and k independently represent an integer of 0 or 1, and j and krepresent 0 when B is (B-2);

l represents 0 or any one of integers of 1 to 16;

R₇(s) and R₈(s) may be the same or different when 1 is 2 or more);

E represents the formula (1a) when Y represents a nitrogen atom;

D represents an oxygen atom, a sulfur atom or the formula (1a);

X represents an oxygen atom, the formula: SOu (wherein u represents aninteger of 0, 1 or 2) or the formula: N—R₉ (wherein R₉ represents ahydrogen atom, a C₁₋₆ alkyl group which may be substituted with G2, or abenzyl group which may be substituted with G2);

Z represents a chroman-2-yl group which is substituted with G3, achroman-4-yl group which is substituted with G3, a2,3-dihydrobenzofuran-2-yl group which is substituted with G3, a2,3-dihydrobenzofuran-3-yl group which is substituted with G3, athiochroman-2-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-2-yl group which is substituted with G3, athiochroman-4-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-3-yl group which is substituted with G3, or a1,3-benzoxathiol-2-yl group which is substituted with G3;

G3 represents the formula: NHR₁₀

{wherein R₁₀ represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, ora benzoyl group (which may be substituted with a nitro group, a halogenatom, a hydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group)};or the formula: OR₁₁{wherein R₁₁ represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, ora benzoyl group (which may be substituted with a hydroxyl group, a C₁₋₆alkoxy group, a halogen atom, or a C₁₋₆ alkyl group)}]or a pharmaceutically acceptable salt thereof.

Second, the present invention is directed to the compound described inclaim 1, wherein Z represents a group represented by the followingformula (Z-1), (Z-2), (Z-3), (Z-4) or (Z-5):

[wherein * represents an asymmetric carbon atom; X₁ represents an oxygenatom or a sulfur atom; R₁₂ to R₃₂ each independently represents ahydrogen atom or a C₁₋₆ alkyl group, and G3 is as defined above] or apharmaceutically acceptable salt thereof.

Third, the present invention is directed to an antioxidant including, asthe active ingredient, one or more compounds or pharmaceuticallyacceptable salts thereof described in (1) or (2).

Third, the present invention is directed to a therapeutic agent forkidney diseases, including the antioxidant described in (3).

Fourth, the present invention is directed to a therapeutic agent forcerebrovascular diseases, including the antioxidant described in (3).

Fifth, the present invention is directed to a therapeutic agent forcirculatory diseases, including the antioxidant described in (3).

Sixth, the present invention is directed to a therapeutic agent forcerebral infarction, including the antioxidant described in (3).

Seventh, the present invention is directed to a therapeutic agent forretinal oxidative damage, including the antioxidant described in (3).

Eighth, the present invention is directed to a therapeutic agentdescribed in (3), wherein the retinal oxidative damage is age-relatedmacular degeneration or diabetic retinopathy.

Ninth, the present invention is directed to a lipoxygenase inhibitorincluding the antioxidant described in (3).

Tenth, the present invention is directed to a 20-hydroxyeicosatetraenoicacid (20-HETE) synthase inhibitor including the antioxidant described in(3).

The phenylazole compounds or pharmaceutically acceptable salts thereofof the present invention have an antioxidation activity which iseffective for treatment of arteriosclerosis, and ischemic organopathysuch as myocardial infarction or cerebral infarction, and treatment ofdiseases such as kidney diseases caused by oxidative cell damage, andcan effectively inhibit retinopathy caused by oxidation due to light,and also can give excellent antioxidants containing the phenylazolecompounds of the present invention and are useful as retinal oxidativedamage inhibitors which exert less side effect, lipoxygenase inhibitors,20-HETE synthase inhibitors, and therapeutic agents for kidney diseases,cerebrovascular or circulatory diseases and cerebral infarction.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides phenylazole compounds represented by theformula (1):

B-D-Z  (1)

[wherein B represents the following formula (B-1), (B-2) or (B-3):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4), or may represent ahydrogen atom or R₁ when B is (B-3):

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl or n-hexyl; aC₁₋₆ alkoxy group which may be substituted with G1, such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy or t-butoxy,a C₁₋₆ alkylsulfonyl group which may be substituted with G1, such asmethylsulfonyl, ethylsulfonyl, propylsulfonyl or butylsulfonyl; or ahalogen atom such as fluorine, chlorine, bromine or iodine; R₆represents a hydrogen atom, a C₁₋₆ alkyl group which may be substitutedwith G1, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, n-pentyl or n-hexyl; a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, such as methylcarbonyl, ethylcarbonyl,propylcarbonyl or butylcarbonyl, or a benzoyl or which may besubstituted with G1, or a tetrahydropyranyl group;

G1 represents a cyano group; a formyl group; a hydroxyl group; aC₁₋₆alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, isobutoxy or t-butoxy; an amino group; a monomethylaminogroup; a dimethylamino group; or a halogen atom such as fluorine,chlorine, bromine or iodine;

s represents 0 or an integer of 1 to 3;

t represents 0 or an integer of 1 or 2;

R₄(s) or R₅(s) may be the same or different when s or t is 2 or more);

an imidazolyl or pyrazolyl group represented by A may have the followingtautomeric structure when R6 is a hydrogen atom;

A is preferably a 1-H-imidazol-2-yl group, a 1-H-imidazol-4-yl group, a1-pyrazole group, a 1-methylimidazol-2-yl group, a 1-methylimidazol-5-ylgroup, a 1-methylimidazol-4-yl group, a 1-methylpyrazol-4-yl group, a1-imidazolyl group, a 1H-pyrazol-5-yl group, a 1H-pyrazol-4-yl group, a1-methylpyrazol-5-yl group, a 1-methylpyrazol-3-yl group, a1-benzoylpyrazol-4-yl group or a 1-(2-tetrahydropyranyl)-pyrazol-3-ylgroup, and A is more preferably a 1-imidazolyl group or a1-H-pyrazol-5-yl group, which is attached to the 3- or 4-position of thebenzene ring;

R₁ represents a halogen atom such as fluorine, chlorine, bromine oriodine; a nitro group; a cyano group; a hydroxyl group; a C₁₋₆ alkylgroup which may be substituted with G2, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl or n-hexyl;C₁₋₆ alkoxy group which may be substituted with G2, such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy or t-butoxy;a C₁₋₆ alkylthio group which may be substituted with G2, such asmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,isobutylthio, sec-butylthio or t-butylthio; a C₁₋₆ alkylcarbonyl groupwhich may be substituted with G2, such as methylcarbonyl, ethylcarbonyl,propylcarbonyl or butylcarbonyl; an amino group (which may besubstituted with one or more C₁₋₆ alkyl groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl orn-hexyl); a benzoyl group which may be substituted with G2; or a benzylgroup which may be substituted with G2;

R₂ represents a C₁₋₆ alkyl group which may be substituted with G2, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl,t-butyl, n-pentyl or n-hexyl;

R₃ represents a hydrogen atom; C₁₋₆ alkyl group which may be substitutedwith G2, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, n-pentyl or n-hexyl; a C₁₋₆ alkylcarbonyl group whichmay be substituted with G2, such as methylcarbonyl, ethylcarbonyl,propylcarbonyl or butylcarbonyl; a benzoyl group which may besubstituted with G2; or a benzyl group which may be substituted with G2;

G2 represents a cyano group; a formyl group; a hydroxyl group; a C₁₋₆alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, isobutoxy or t-butoxy; a C₁₋₆ alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy,butoxycarbonyl or t-butoxycarbonyl; a nitro group; an amino group; amonomethylamino group; a dimethylamino group; or a halogen atom, such asfluorine, chlorine, bromine or iodine;

m represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when m is 2 or more;

n represents 0 or an integer of 1 to 10, and R₂(s) may be the same ordifferent when n is 2 or more;

o represents an integer of 1 or 2;

p represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when p is 2 or more;

q and r each independently represents an integer of 1 or 2;

in the formula (B-1), the dotted line represents a single bond or adouble bond and does not simultaneously represent a double bond;

Y represents a carbon atom or a nitrogen atom, which may have asubstituent or a multiple bond that satisfies a valence;

E represents an oxygen atom, a sulfur atom or the following formula (1a)when Y represents a carbon atom;

(wherein R₆₀ represents a hydrogen atom; a C₁₋₆ alkylcarbonyl group or abenzoyl group (which may be substituted with a nitro group; a halogenatom such as fluorine, chlorine, bromine or iodine; a hydroxyl group; aC₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, isobutoxy or t-butoxy; or a C₁₋₆ alkyl group such as methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl);and R₇ and R₈ each independently represents a hydrogen atom; a cyanogroup; a hydroxyl group; a halogen atom such as fluorine, chlorine,bromine or iodine; a C₁₋₆ alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; a C₁₋₆ alkoxy groupsuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,isobutoxy or t-butoxy; a C₂₋₆ alkenyl group such as ethenyl, 1-propenyl,2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,4-hexenyl or 5-hexenyl; a C₂₋₆ alkynyl group such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-pentynyl,1-hexynyl or 1,1-dimethyl-2-butynyl; a C₂₋₆ alkenyloxy group such asallyloxy, 2-propenyloxy, 2-butenyloxy or 2-methyl-3-propenyloxy; a C₂₋₆alkynyloxy group such as 2-propynyloxy, 2-butynyloxy or1-methyl-2-propynyloxy; a C₁₋₆ acyloxy group such as acetoxy,propionyloxy or butyryloxy; a C₃₋₆ cycloalkyl group which may besubstituted with G2, such as cyclopropyl, 1-methylcyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl; or a phenyl group which may be substituted with G2;

j and k independently represent an integer of 0 or 1, and j and krepresent 0 when B is (B-2);

l represents 0 or an integer of 1 to 16;

R₇(s) and R₈(s) may be the same or different when 1 is 2 or more);

E represents the formula (1a) when Y represents a nitrogen atom;

D represents an oxygen atom, a sulfur atom or the formula (1a);

X represents an oxygen atom, the formula: SOu (wherein u represents 0 oran integer of 1 or 2) or the formula: N—R₉ (wherein R₉ represents ahydrogen atom, a C₁₋₆alkyl group which may be substituted with G2, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or,t-butyl; or a benzyl group which may be substituted with G2);

Z represents a chroman-2-yl group which is substituted with G3, achroman-4-yl group which is substituted with G3, a2,3-dihydrobenzofuran-2-yl group which is substituted with G3, a2,3-dihydrobenzofuran-3-yl group which is substituted with G3, athiochroman-2-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-2-yl group which is substituted with G3, athiochroman-4-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-3-yl group which is substituted with G3, or a1,3-benzoxathiol-2-yl group which is substituted with G3;

Z is preferably the following formula (Z-1), (Z-2), (Z-3), (Z-4) or(Z-5);

[wherein * represents an asymmetric carbon atom; X₁ represents an oxygenatom or a sulfur atom; R₁₂ to R₃₂ each independently represents ahydrogen atom, or a C₁₋₆ alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl];

G3 represents the formula: NHR₁₀

{wherein R₁₀ represents a hydrogen atom; a C₁₋₆ alkylcarbonyl group suchas methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy,butoxycarbonyl or t-butoxycarbonyl; or a benzoyl group (which may besubstituted with a nitro group; a halogen atom such as fluorine,chlorine, bromine or iodine; a hydroxyl group; a C₁₋₆ alkoxy group; or aC₁₋₆ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl or t-butyl)};or the formula: OR₁₁{wherein R₁₁ represents a hydrogen atom; a C₁₋₆ alkylcarbonyl group suchas methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy,butoxycarbonyl or t-butoxycarbonyl; or a benzoyl group (which may besubstituted with a hydroxyl group; a C₁₋₆ alkoxy group; a nitro group; ahalogen atom such as fluorine, chlorine, bromine or iodine; or a C₁₋₆alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl or t-butyl)}]or pharmaceutically acceptable salts thereof.

(Process for Production of Compounds)

The compound in which the moiety B is B-1 among phenylazole compoundsrepresented by the formula (1) of the present invention can be producedby the following production processes 1 to 7.

Production Process 1: Step 1

{in the formula (2), A, E, Y, R1, R2, m, n and o are the same as A, E,Y, R1, R2, m, n and o in the formula (1) and, in the formula (3), thereis attained equivalence between D in the formula (1) and the formula(C═O)-D′, and Z′ represents Z when G3 in the formula (Z-1), (Z-2),(Z-3), (Z-4) or (Z-5) is a nitro group or OR₁₁}

In the step 1, by dehydrocondensing carboxylic acid represented by theformula (3) with an amine represented by the formula (2) using aconventional process, there can be obtained a phenylazole compoundrepresented by the formula (1′) (wherein A, E, Y, R1, R2, m, n and o arethe same as A, E, Y, R1, R2, m, n and o in the formula (2), and D′ andZ′ are the same groups as for D′ and Z′ in the formula (3)) of thepresent invention.

This dehydrocondensation reaction can be carried out in the presence ofa suitable condensing agent. In this case, as the condensing agent, forexample, 1,3-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline can be used.

In this reaction, the reaction can be allowed to proceed more quickly bythe coexistence of N-hydroxysuccinic acidimide, 1-hydroxybenzotriazoleand 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine in the reactionsystem.

The reaction solvent is not specifically limited as far as it is asolvent which is inactive to the reaction, and examples thereof includeethers such as diethyl ether, tetrahydrofuran (hereinafter abbreviatedto THF) and 1,4-dioxane; aromatic hydrocarbons such as benzene, tolueneand xylene; halogenated hydrocarbons such as dichloromethane, chloroformand 1,2-dichloroethane; acetonitrile, dimethyl formamide (hereinafterabbreviated to DMF), dimethyl sulfoxide (hereinafter abbreviated toDMSO) and pyridine.

The reaction is carried out at a temperature within a range from −15° C.to about a boiling point of the solvent, and preferably from 0 to 80° C.

Production Process 2:

Alternatively, the compound can also be produced according to thefollowing reaction scheme.

{in the formula (2), A, E, Y, R1, R2, m, n and o are the same as A, E,Y, R1, R2, m, n and o in the formula (1) and, in the formula (3′), thereis attained equivalence between D in the formula (1) and the formula(C═O)-D′, and Z′ represents Z when G3 in the formula (Z-1), (Z-2),(Z-3), (Z-4) or (Z-5) is a nitro group or OR₁₁}

That is, an acid chloride (4) is obtained from a carboxylic acidderivative represented by the formula (3′) using a halogenating agentsuch as thionyl chloride, phosphorus pentachloride or oxalic aciddichloride, and the resulting acid chloride is reacted with an aminerepresented by the formula (2) in an inactive organic solvent in thepresence of a base to obtain a phenylazole compound represented by theformula (1′) (wherein A, E, Y, R1, R2, m, n and o are the same as A, E,Y, R1, R2, m, n and o in the formula (2,) and D′ and Z′ are the samegroups as for D′ and Z′ in the formula (3)) of the present invention.

The reaction solvent is not specifically limited as far as it is asolvent which is inactive to the reaction, and there can be used, forexample, ethers such as diethyl ether, THF and 1,4-dioxane; aromatichydrocarbons such as benzene, toluene and xylene; halogenatedhydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane;acetonitrile, DMF, DMSO and pyridine.

Examples of the base used in the reaction include amines such astriethylamine, pyridine and 1,8-diazabicyclo[5.4.0]undec-7-ene(hereinafter abbreviated to DBU); and inorganic bases such as sodiumhydrogen carbonate, sodium carbonate, potassium carbonate and sodiumhydroxide.

The reaction is carried out at a temperature within a range from −15° C.to about a boiling point of the solvent, and preferably from 0 to 80° C.

Production Process 3:

{in the formula (2), A, E, Y, R1, R2, m, n and o are the same as A, E,Y, R1, R2, m, n and o in the formula (1) and, in the formula (5), thereis attained equivalence between D in the formula (1) and the formulaCH₂-D′, and Z′ represents Z when G3 in the formula (Z-1), (Z-2), (Z-3),(Z-4) or (Z-5) is a nitro group or OR₁₁}

That is, by performing reductive amination of an aldehyde represented bythe formula (5) and an amine represented by the formula (2) using aconventional process, there can be obtained a phenylazole compoundrepresented by the formula (1″) (wherein A, E, Y, R1, R2, m, n and o arethe same as A, E, Y, R1, R2, m, n and o in the formula (2), and D′ andZ′ are the same groups as for D′ and Z′ in the formula (5)) of thepresent invention.

This reductive amination reaction can be carried out by adding areducing agent in the presence of a suitable acid catalyst. In thiscase, examples of the acid catalyst include organic acids such as aceticacid and p-toluenesulfonic acid; and inorganic acids such as sulfuricacid and hydrochloric acid. Examples of the reducing agent include NaBH₄and sodium triacetoxyborohydride.

The reaction solvent is not specifically limited as far as it is asolvent which is inactive to the reaction, and examples thereof includeethers such as diethyl ether, THF and 1,4-dioxane; aromatic hydrocarbonssuch as benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane; acetonitrile, DMF,DMSO and pyridine.

The reaction is carried out at a temperature within a range from −15° C.to about a boiling point of the solvent, and preferably roomtemperature.

Production Process 4: Step 2

An aniline compound as the phenylazole compound of the present inventioncan be produced by the following process.

{in the formula (1″), A, E, Y, R1, R2, m, n and o are the same as A, E,Y, R1, R2, m, n and o in the formula (1), and Z′ represents Z when G3 inthe formula (Z-1), (Z-2), (Z-3), (Z-4) or (Z-5) is a nitro group}

That is, in the step 2, by hydrogenating the phenylazole compound havinga nitro group represented by the formula (1″) obtained in the productionprocesses 1 to 3 of the present invention using a catalyst, there isobtained an aniline compound, as the phenylazole-based compoundrepresented by the formula (1) in which a nitro group of the substituentG3 in Z′ is converted into NHR₁₀ of the present invention.

Examples of the catalyst include palladium carbon, platinum dioxide andRaney nickel.

As the reaction solvent, there can be used alcohols such as methanol andethanol; ethers such as diethyl ether, THF and 1,4-dioxane; aromatichydrocarbons such as benzene, toluene, xylene and cyclohexane; amidessuch as DMF; organic acids such as formic acid and acetic acid; esterssuch as ethyl acetate; and solvent mixtures thereof.

The reaction is carried out at a temperature within a range from 0° C.to about a boiling point of the solvent, and preferably from 20 to 80°C.

Production Process 5:

{in the formula (1″), A, E, Y, R1, R2, m, n and o are the same as A, E,Y, R1, R2, m, n and o in the formula (1), and Z′ represents Z when G3 inthe formula (Z-1), (Z-2), (Z-3), (Z-4) or (Z-5) is a nitro group}

That is, by hydrogenating the phenylazole compound having a nitro grouprepresented by the formula (1″) of the present invention using a metalcatalyst and an acid, there is obtained an aniline compound, as thephenylazole compound represented by the formula (1) in which a nitrogroup of the substituent G3 in Z′ is converted into NHR₁₀ of the presentinvention.

Examples of the metal catalyst include stannous chloride.

Examples of the acid include sulfuric acid or hydrochloric acid.

As the reaction solvent, there can be used alcohols such as methanol andethanol; ethers such as diethyl ether, THF and 1,4-dioxane; hydrocarbonssuch as benzene, toluene, xylene and cyclohexane; amides such as DMF;and solvent mixtures thereof.

The reaction is carried out at a temperature within a range from 0° C.to about a boiling point of the solvent, and preferably from 60 to 80°C.

Production Process 6: Step 1:

{in the formula (1c′), A, E, R1, R2, m, n and o are the same as A, E,R1, R2, m, n and o in the formula (7a); D is the same group as for D inthe formula (1); Z′ represents Z when G3 in the formula (Z-1), (Z-2),(Z-3), (Z-4) or (Z-5) is a nitro group or OR₁₁, in the formula (6), E,R₁, R₂, m, n and o are the same as E, R₁, R₂, m, n and o in the formula(1); Y represents a carbon atom; R₃₄ represents an acyl group; R₃₃represents a halogen atom; in the formula (1′b), R₄ and s are the sameas R₄ and s in the formula (A-1); in the formula (7), A, E, R₁, R₂, m,n, R₃₄ and o are the same as A, E, R₁, R₂, m, n, R₃₄ and o in theformula (6); A represents an imidazolyl group derived from the formula(1′b); in the formula (7a), A, E, R1, R2, m, n and o are the same as A,E, R1, R2, m, n and in the formula (7); in the formula (8), D is thesame group as for D in the formula (1); Z′ represents Z when G3 in theformula (Z-1), (Z-2), (Z-3), (Z-4) or (Z-5) is a nitro group or OR₁₁;and R₃₄ represents a perfluoroalkyl group}

The phenylazole compound represented by the formula (1c′) can beproduced by the process comprising the step 1 of reacting a compoundrepresented by the formula (6) with an imidazole compound represented bythe formula (1′b) in a solvent in the presence of a catalyst, anddehydrating and deacylating a compound represented by the formula (7) toobtain a compound represented by the formula (7a), and the second stepof reacting a compound represented by the formula (7a) with aperfluoroalkane sulfonate ester compound represented by the formula (8)in a solvent.

In the compound represented by the formula (6) used as a raw material inthe step 1, examples of the acyl group as for R₃₄ include acetyl group,propionyl group and butyryl group and examples of the halogen atom asfor R₃₃ include bromine atom, chlorine atom, fluorine atom and iodineatom. The compound having such a group represented by the formula (6)can be reacted with the imidazole compound represented by the formula(1′b) in a BTX solvent such as xylene, toluene or mesitylene using1,10-phenanthroline, 1,5-diphenyl-1,4-pentadien-3-one, cesium carbonateor a copper (I) trifluoromethane sulfonate benzene complex. The reactionis carried out by heating at reflux (a temperature corresponding to aboiling point of the solvent within a range from 100 to 150° C.) in anargon gas flow to obtain a product represented by the formula (7). Thereaction product represented by the formula (7) can be dehydrated byheating at reflux using concentrated hydrochloric acid and, after thereaction, the reaction product is neutralized with an alkali to obtain acompound represented by the formula (7a).

Examples of the perfluoroalkane sulfonate ester compound represented bythe formula (8) used in the step 2 include those having atrifluoromethyl group or a perfluoroethyl group as R₃₅. Among thesegroups, a trifluoromethyl group is preferable. Theperfluoroalkanesulfonic acid compound can be reacted with the compoundrepresented by the formula (7a) obtained in the step 1 by heating atreflux (a temperature within a range from 100 to 150° C.) in anether-based solvent such as acetonitrile, dioxane or THF, or a BTX-basedsolvent such as benzene or toluene using, as a catalyst, a base such assodium carbonate or potassium carbonate.

Production Process 7:

The aniline compound as the phenylazole compound of the presentinvention can be produced by the following process.

Step 3:

{in the formula (1c), A, E, Y, R1, R2, m, n and o are the same as A, E,Y, R1, R2, m, n and o in the formula (1c′), Z represents a group inwhich a nitro group of the substituent G3 in Z′ in the formula (1c′) isconverted into NHR₁₀ and, in the formula (1d), A, E, Y, R₁, R₂, m, n ando are the same as A, E, Y, R1, R₂, m, n and o in the formula (1c)}

That is, in the step 3, the phenylazole compound having a nitro grouprepresented by the formula (1c′) obtained in the step 2 is reduced toobtain a phenylazole-based compound represented by the formula (1c) inwhich a nitro group of the substituent G3 in Z′ is converted into NHR₁₀.The phenylazole-based compound represented by the formula (1c′) can becarried out by the process of heating at reflux (a temperature within arange from 100 to 150° C.) using a catalyst such as stannous chloridedihydrate and neutralizing with an alkali after the completion of thereaction.

Furthermore, the reaction of reducing the phenylazole-based compoundrepresented by the formula (1c) obtained in the step 3 to obtain aphenylazole-based compound represented by the formula (1d) can becarried out by hydrogenating in a solvent, for example, alcohol such asmethanol or ethanol, organic acid such as acetic acid, or a solventmixture thereof at room temperature or 0 to 60° C. using a catalyst suchas palladium.

A 3-imidazole compound can be synthesized by the same process asdescribed above. Also an amide type compound can be synthesized by thesame process as described above.

The compound in which the moiety B is (B-2) among phenylazole compoundsrepresented by the formula (1) of the present invention can be producedas shown in the following production processes 8 to 11.

Production Process 8:

{in the formula (9), A, R1, R9 and m are the same as A, R1, R9 and m inthe formula (1) and, in the formula (10), there is attained equivalencebetween D in the formula (1) and the formula CH₂-D′, and Z′ represents Zwhen G3 is a nitro group or OR₁₁ in the Z in the formula (1)}

That is, a phenylazole derivative (1e) represented by the formula (1) ofthe present invention is obtained by the reductive amination reactionthorough a conventional process using an aldehyde represented by formula(10) and an amine represented by the formula (9) as a starting material.

Such a reductive amination reaction can be carried by adding a reducingagent in the presence of a suitable acid catalyst. In this case,examples of the acid catalyst include organic acids such as acetic acidand p-toluenesulfonic acid; and inorganic acids such as sulfuric acidand hydrochloric acid. Examples of the reducing agent include NaBH₄ andsodium triacetoxyborohydride.

The reaction solvent is not specifically limited as far as it is asolvent which is inactive to the reaction, and examples thereof includeethers such as diethyl ether, THF and 1,4-dioxane; aromatic hydrocarbonssuch as benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane; acetonitrile, DMF,DMSO and pyridine.

The reaction is carried out at a temperature within a range from −15° C.to about a boiling point of the solvent, and preferably roomtemperature.

Production Process 9:

The phenylazole derivative represented by the formula (1) of the presentinvention can be produced by the following process.

{in the formula (9′), A, R1, m and X are the same as A, R1, m and X informula (1) and, in the formula (10′), D is the same as D in the formula(1), Z′ represents Z when G3 is a nitro group or OR₁₁ in Z in theformula (1), and R₃₆ represents a leaving group derived from an alcohol,for example, halogen such as chlorine, bromine or iodine; or a sulfonateester such as methane sulfonate, toluene sulfonate or trifluoromethanesulfonate}

That is, a compound (1e′) as the phenylazole derivative represented bythe formula (1) of the present invention is obtained by alklylating acompound represented by the formula (9′) with a compound represented bythe formula (10′).

Such a reaction can be carried out in an inactive solvent, for example,ethers such as diethyl ether, THF and 1,4-dioxane; aromatic hydrocarbonssuch as benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane; acetonitrile, DMFand DMSO at a temperature within a range from −15° C. to about a boilingpoint of the solvent, preferably from 0 to 80° C. in the presence of abase, for example, amines such as triethylamine, pyridine and DBU; andinorganic bases such as sodium hydrogen carbonate, sodium carbonate,potassium carbonate and sodium hydroxide.

A 4-(imidazol-1-yl)thiophenol represented by the formula (6′) can beproduced by a known process described in the document (for example,Specification of Germany Patent Publication No. 2267101).

Production Process 10:

The phenylazole derivative represented by the formula (1) of the presentinvention can be produced as shown in the following scheme.

{in the formula (10″), R₉ is the same as R₉ in the formula (1), in theformula (9″), A, R1, m and D are the same as A, R1, m and D in theformula (1), Z′ represents Z when G3 is a nitro group or a OR₁₁ group inZ in the formula (1), in the formula (10″), R₃₇ represents a leavinggroup, for example, halogen such as chlorine, bromine or iodine, and asulfonate ester such as methane sulfonate, toluene sulfonate ortrifluoormethane sulfonate}

That is, a compound (1e″) as the phenylazole derivative represented bythe formula (1) of the present invention is obtained by alklylating acompound represented by the formula (9″) with a compound represented bythe formula (10″).

Such a reaction can be carried out in an inactive solvent, for example,ethers such as diethyl ether, THF and 1,4-dioxane; aromatic hydrocarbonssuch as benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane; acetonitrile, DMFand DMSO at a temperature within a range from −15° C. to about a boilingpoint of the solvent, preferably from 0 to 100° C. in the presence of abase, for example, amines such as triethylamine, pyridine and DBU; andinorganic bases such as sodium hydrogen carbonate, sodium carbonate,potassium carbonate and sodium hydroxide.

Production Process 11:

The phenylazole derivative represented by the formula (1) of the presentinvention can be produced as shown in the following scheme.

{in the formula (1e′″), A, R1, m, D and X are the same as A, R1, m, Dand X in the formula (1), and Z′ represents Z when G3 is a nitro groupin Z in the formula (1)}

According to this reductive reaction, there can be obtained an anilinecompound (1f) as the phenylazole derivative represented by the formula(1) of the present invention in which a nitro group of the substituentG3 in Z′ is converted into NHR₁₀ by hydrogenating a nitro compoundrepresented by the formula (1e′″) using a catalyst or reducing using areducing agent.

Examples of the catalyst used for hydrogenation include palladiumcarbon, palladium hydroxide, platinum dioxide and Raney nickel.

Examples of the reaction solvent include alcohols such as methanol andethanol; ethers such as diethyl ether, THF and 1,4-dioxane; hydrocarbonssuch as benzene, toluene, xylene and cyclohexane; amides such as DMF;organic acids such as formic acid and acetic acid; esters such as ethylacetate, and solvent mixtures thereof.

When using these reducing agents, the reduction can be carried out in analcohol such as methanol or ethanol using hydrochloric acid and stannouschloride, or carried out in a solvent mixture of acetone or methyl ethylketone and water using acetic acid and iron.

The reaction can be carried out at a temperature within a range from 0°C. to about a boiling point of the solvent.

In the present invention, the objective product can be obtained bycarrying out a conventional work-up after the completion of thereaction.

The compound in which the moiety B is (B-3) represented by the formula(1) among the phenylazole-based compounds of the present invention canbe produced by the following production processes 12 to 15.

Production Process 12:

{in the formula (1g), A, R1, R3, p, q and r are the same as A, R1, R3,p, q and r in the formula (1), in the formula (3) and the formula (4),there is attained equivalence between D in the formula (1) and theformula (C═O)-D′, and Z′ represents Z when G3 is a nitro group or OR₁₁in Z in the formula (1)}

That is, an amide derivative as the nitro compound represented by theformula (1g) can be obtained by halogenating a carboxylic acidderivative represented by the formula (3) using a halogenating agentsuch as thionyl chloride, phosphorus pentachloride or oxalic aciddichloride to obtain an acid chloride (4), and reacting the resultingacid chloride with an amine represented by the formula (11) in aninactive organic solvent in the presence of a base.

The reaction solvent is not specifically limited as far as it is asolvent which is inactive to the reaction and, for example, there can beused ethers such as diethyl ether, THF and 1,4-dioxane; aromatichydrocarbons such as benzene, toluene and xylene; halogenatedhydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane;acetonitrile, DMF, DMSO and pyridine.

Examples of the base used in the reaction include amines such astriethylamine, pyridine and DBU; and inorganic bases such as sodiumhydrogen carbonate, sodium carbonate, potassium carbonate and sodiumhydroxide.

The reaction is carried out at a temperature within a range from −15° C.to about a boiling point of the solvent, and preferably from 0 to 80° C.

Production Process 13:

Alternatively, the compound can also be produced according to thefollowing reaction scheme.

{in the formula (11), A, R1, R3, p, q and r are the same as A, R1, R3,p, q and r in the formula (1), in the formula (3), there is attainedequivalence between D in the formula (1) and the formula (C═O)-D′, andZ′ represents Z when G3 is a nitro group or OR₁₁ in Z in the formula(1)}

That is, an amide derivative as the nitro compound represented by theformula (1g) is obtained by dehydrocondensing a carboxylic acidrepresented by the formula (3) with an amine represented by the formula(11) using a conventional process.

This dehydrocondensation reaction can be carried out in the presence ofa suitable condensing agent. In this case, examples of the condensingagent include 1,3-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

In this reaction, the reaction can be allowed to proceed more quickly bythe coexistence of N-hydroxysuccinic acid imide, 1-hydroxybenzotriazoleand 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine in the reactionsystem.

The reaction solvent is not specifically limited as far as it is asolvent which is inactive to the reaction, and examples thereof includeethers such as diethyl ether, THF and 1,4-dioxane; aromatic hydrocarbonssuch as benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane; acetonitrile, DMF,DMSO and pyridine.

The reaction is carried out at a temperature within a range from −15° C.to about a boiling point of the solvent, and preferably from 0 to 80° C.

The compound represented by the general formula (2) can be produced by aknown process described in the document [for example, Journal ofMedicinal Chemistry, 1980, Vol. 23, P. 635-643, Synthesis, 1977, P.645-646, and Journal of Medicinal Chemistry, 1977, Vol. 20, P. 600-602.

Production Process 14:

Alternatively, the compound can also be produced according to thefollowing reaction scheme.

{in the formula (11), A, R1, R3, p, q and r are the same as A, R1, R3,p, q and r in the formula (1), in the formula (5), there is attainedequivalence between D in the formula (1) and the formula CH₂-D′, and Z′represents Z when G3 is a nitro group or OR₁₁ in Z in the formula (1)}

That is, an amine derivative as the nitro compound represented by theformula (1h) can be obtained by reductive amination of an aldehyderepresented by the formula (5) and an amine represented by the formula(11) using a conventional process.

This reductive amination reaction can be carried out by adding areducing agent in the presence of a suitable acid catalyst. In thiscase, examples of the acid catalyst include organic acids such as aceticacid and p-toluenesulfonic acid; and inorganic acids such as sulfuricacid and hydrochloric acid. Examples of the reducing agent includesodium borohydride and sodium triacetoxyborohydride.

The reaction solvent is not specifically limited as far as it is asolvent which is inactive to the reaction, and examples thereof includeethers such as diethyl ether, THF and 1,4-dioxane; aromatic hydrocarbonssuch as benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane; acetonitrile, DMF,DMSO and pyridine.

The reaction is carried out at a temperature within a range from −15° C.to about a boiling point of the solvent, and preferably roomtemperature.

Production Process 15:

{in the formula, A, D″, Z, R1, R3, p, q and r are the same as A, D, Z,R1, R3, p, q and r in the formula (1), and Z′ represents Z when G3 is anitro group in Z in the formula (1)}

That is, an aniline compound represented by the formula (1j) is obtainedby hydrogenating a nitro compound represented by the formula (1i) suchas formula (1g) or (1h) using a catalyst.

Examples of the catalyst include palladium carbon, platinum dioxide andRaney nickel.

As the reaction solvent, there can be used alcohols such as methanol andethanol; ethers such as diethyl ether, THF and 1,4-dioxane; hydrocarbonssuch as benzene, toluene, xylene and cyclohexane; amides such as DMF;organic acids such as formic acid and acetic acid; esters such as ethylacetate, and solvent mixtures thereof.

The reaction is carried out at a temperature within a range from 0° C.to about a boiling point of the solvent, and preferably from 20 to 80°C.

In the present invention, the objective product can be obtained bycarrying out a conventional work-up after the completion of thereaction.

The structure of the compounds of the present invention compound wasdecided by IR, NMR and MS.

In the phenylazole compounds represented by the formula (1) of thepresent invention, some optical active substances and tautomers canexist. These optical active substances and tautomers are included in thescope of the present invention.

Pharmaceutically acceptable salts of the phenylazole compoundsrepresented by the formula (1) of the present invention are notspecifically limited as far as they are salts of the phenylazolecompounds represented by the formula (1) and are pharmaceuticallyacceptable, and examples of salts include salts of inorganic acids suchas hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid;and salts of organic acids such as acetic acid, propionic acid, lacticacid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylicacid, nicotinic acid and heptagluconic acid. These salts can be easilyproduced by a conventional synthetic chemical technique.

Since the phenylazole compounds of the present invention have anantioxidation action, the phenylazole compounds can inhibit the onsetand progression of lesion of arteriosclerosis by preventing oxidativedenaturation of low density lipoprotein (hereinafter abbreviated to LDL)and can be applied to a therapeutic agent for arteriosclerosis, and alsouseful as therapeutic agents for various diseases ascribable tooxidation, for example, senile dementing diseases, cardiac disease,cancer, diabetes mellitus, digestive organ diseases, burn, ophthalmicdiseases and kidney diseases. In ischemic organopathies such as cerebralinfarction and myocardial infarction, various active oxygens aregenerated on blood reperfusion of the ischemia site and tissue disorderis aggravated by cellular membrane disruption due to the lipidperoxidation reaction. However, the phenylazole compounds of the presentinvention can remove various active oxygens and lipid peroxidations bythe antioxidation activity, and thus the phenylazole compounds canprevent tissue disorder of the ischemic lesioned part and can be appliedas a therapeutic agent for ischemic organopathy. The phenylazolecompounds of the present invention have an lipoxygenase inhibitoryaction and a 20-HETE synthase inhibitory action, and can inhibitconversion of arachidonic acid into HPETE by inhibiting an action oflipoxygenase and can inhibit the production of 20-HETE by inhibiting20-HETE synthase. The compounds of the present invention also includecompounds which exert less dopamine release inhibitory action and hardlycause side effects such as parkinsonism.

Furthermore, the phenylazole compounds of the present invention can beused for prophylaxis and treatment of diseases caused by retinaloxidative damage; connective tissue diseases such as diabetes mellitus,hypertension, arteriosclerosis, anemia, leukaemia, generalized lupuserythematosus and scleroderma; vascular damage and pro-inflammatory anddenaturation lesion of the retina caused by systematic diseases such asinborn error of metabolism, for example, Tay-Sacks and Vogt-Spielmeyer;disorders of retinal vessel, such as prematurity retinopathy, occlusionof retinal vein, occlusion of retinal artery and periphlebitis retinae;inflammation and denaturation of the retina caused by retinodialysis andexternal injury; degenerative diseases of the retina caused by aging,such as aging macular degeneration; and diseases of the retinal focus,such as congenital retinal degeneration diseases, and are particularlyuseful as an aging macular degeneration occurred by photooxidationdisorder; and therapeutic agents for diabetic retinopathy.

(Antioxidants)

The antioxidants of the present invention are not specifically limitedas far as they contain one or more phenylazole compounds having theabove antioxidation action of the present invention or pharmaceuticallyacceptable salts thereof as the active ingredient, and can beadministered as drugs for the above diseases in any form. For example,the antioxidants can be orally, pernasally, parenterally, locally,percutaneously or transrectallly administered in the dosage form ofsolid, semi-solid, lyophilized powder or liquid, for example, tablets,suppositories, pills, ointments, hard capsules, powders, solutions,injections, suspensions, aerosols, and sustained-release preparations,and can be in suitable dosage which can be administered simply in anaccurate dose.

The antioxidants of the present invention can be formed into acomposition which contains the active ingredient, a conventional carrieror excipient for drug, other drugs and an adjuvant as far as thesecomponents do not react with other components. Such a compositioncontains 1 to 99% by weight of the active ingredient and 99 to 1% byweight of a suitable carrier or excipient for drug, and preferablycontains 5 to 75% by weight of the active ingredient and balance of asuitable carrier or excipient for drug, according to the administrationmode.

To the antioxidants of the present invention, a small amount ofadjuvants such as wetting agents, emulsifiers, pH buffering agents andantioxidizing agent, for example, citric acid, sorbitan monolaurate,triethanolamine oleate and butylated hydroxytoluene can be optionallyadded as far as these adjuvants do not react with other components,regardless of the dosage form.

These pharmaceutical preparations can be produced by a conventionalprocess according to the description taught in Remington'sPharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton,Pa., published in 1990.

In the antioxidants of the present invention, a therapeuticallyeffective amount of the compounds represented by the formula (1) orpharmaceutically acceptable salts thereof varies depending onindividuals and pathological conditions of diseases to be treated.Usually, a therapeutically dose per day of one or more compoundsrepresented by the formula (1) or pharmaceutically acceptable saltsthereof is within a range from 0.14 to 14.3 mg/day/body weight (kg),preferably from 0.7 mg to 10 mg/day/body weight (kg), more preferablyfrom 1.4 mg to 7.2 mg/day/body weight (kg). In case of administering tothe human having a body weight of 70 kg, the dose of the compounds ofthe formula (1) or pharmaceutically acceptable salts thereof is within arange from 10 mg to 1.0 g per day, preferably from 50 mg to 700 mg perday, and more preferably from 100 mg to 500 mg per day. This dose ismerely a measure and can deviate from the above range according to thepathological conditions of the treatment.

Preferable administration path of the antioxidants of the presentinvention is oral administration and examples of the excipient to beapplied to the antioxidants for oral administration includeconventionally used any excipients, for example, mannitol, lactose,starch, gelatinized starch, magnesium stearate, saccharin sodium, talc,cellulose ether derivative, glucose, gelatin, sucrose, citrate andpropyl gallate which are used for drugs. The antioxidants for oraladministration can contain diluents such as lactose, sucrose anddicalcium phosphate, disintegrators such as croscarmellose sodium orderivative thereof, and binders such as magnesium stearate, lubricantssuch as starch, gum arabic, polyvinyl pyrrolidone, gelatin and celluloseether derivative.

When the antioxidants of the present invention are applied to theinjection, sterile aqueous or non-aqueous solutions, suspensions andemulsions are preferably contained. As the diluent of the aqueoussolutions and suspensions, diluent, for example, distilled water orphysiological saline for injection can be used. As the diluent of thewater-insoluble solutions and suspensions, for example, propyleneglycol, polyethylene glycol, vegetable oil such as olive oil, alcoholssuch as ethanol, and Polysolvate (trade name) can be used. Theinjections may further contain additives such as isotonizing agents,antiseptics, wetting agents, emulsifiers, dispersing agent, stabilizers(for example, lactose), solubilizers and solubilizing auxiliary agents.These additives can also be used by dissolving in sterile water or asterile solvent for injection after producing a solid composition of afilter material and a sterilizer which pass through a bacteria holdingfilter.

When the antioxidants of the present invention are applied to thesuppository, the suppository is obtained by using, as a carrier, acarrier which gradually dissolves in the body such as polyoxyethyleneglycol or polyethylene glycol (hereinafter abbreviated to PEG), forexample, PEG1000 (96%) or PEG4000 (4%) and dispersing 0.5 to 50% byweight of the compounds of the formula (1) or pharmaceuticallyacceptable salts thereof in the carrier.

When the antioxidants of the present invention are applied to thesolution, the solution is preferably obtained by using, as a carrier,water, saline, aqueous dextrose solution, glycerol or ethanol, anddispersing 0.5 to 50% by weight of the compounds of the formula (1) orpharmaceutically acceptable salts thereof and any adjuvant for drug inthe carrier to give a solution or suspension.

(Retinal Oxidative Damage Inhibitors)

The retinal oxidative damage inhibitors of the present invention are notspecifically limited as far as they contain the antioxidants containingthe phenylazole compounds having the antioxidation action orpharmaceutically acceptable salts thereof of the present invention asthe active ingredient, and the administration mode, the dosage form andthe dose may be the same as those in case of the antioxidants. Theretinal oxidative damage inhibitors can contain the same components forpreparation, carriers and adjuvants as those in case of the antioxidantsand may further contain excipients, disintegrators, binders and one ormore retinal oxidative damage inhibitors which do not react with theactive ingredients, and also may contain components having other drugpotency. The dosage form may be the same as those in case of theantioxidants, and may be the other dosage form such as eye drop or eyeointment.

When the retinal oxidative damage inhibitors of the present inventionare applied to the eye drop, the phenylazole compounds of the presentinvention are added to a base solvent used usually to give an aqueoussolution or suspension and then the pH is adjusted within a range from 4to 10, and preferably from 5 to 9. The eye drop is preferably subjectedto a sterilization treatment so as to obtain a sterile product, and thesterilization treatment can be carried out in any stage of theproduction process. The concentration of the phenylazole compounds ofthe present invention in the eye drop is within a range from 0.001 to 3%(W/V), and preferably from 0.01 to 1% (W/V). The dose varies dependingon the degree of symptoms and constitution of patients and the eye dropmay be applied 1 to 4 times per day in an amount of several drops. Thisdose is merely a measure and can deviate from the above range accordingto the pathological conditions of the treatment.

To the eye drop, various additives such as buffering agents, isotonizingagents, antiseptics, pH adjustors, thickeners, chelating agents and,solubilizing agents may be appropriately added as far as thesecomponents do not react with phenylazole compounds of the presentinvention. Examples of the buffering agent include citrate bufferingagent, tartaric acid buffering agent, acetate buffering agent and aminoacid. Examples of the isotonizing agent include saccharides such assorbitol, glucose and mannitol, polyhydric alcohols such as glycerin,polyethylene glycol and propylene glycol, and salts such as sodiumchloride. Examples of the antiseptic include paraoxybenzoate esters suchas methyl paraoxybenzoate and ethyl paraoxybenzote, benzyl alcohol,phenethyl alcohol, sorbic acid or salts thereof. Examples of the pHadjustor include phosphoric acid and sodium hydroxide. Examples of thethickener include hydroxyethyl cellulose, hydroxypropyl cellulose,methyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl celluloseand salts thereof. Examples of the chelating agent include sodiumedetate, sodium citrate and condensed sodium phosphate, and examples ofthe solubilizing agent include ethanol and polyoxyethylene hardenedcastor oil.

When the retinal oxidative damage inhibitors of the present inventionare applied to the eye ointment, the eye ointment is obtained by mixingthe phenylazole compounds of the present invention with an eye ointmentbase such as purified lanolin, white petrolatum, macrogol, plastibase orliquid paraffin, and is preferably subjected to a sterilizationtreatment so as to obtain a sterile product. The concentration of thephenylazole compounds of the present invention in the eye ointment iswithin a range from 0.001 to 3% (W/V), and preferably from 0.01 to 1%(W/V). The dose varies depending on the degree of symptoms andconstitution of patients and the eye ointment may be applied 1 to 4times per day. This dose is merely a measure and can deviate from theabove range according to the pathological conditions of the treatment.

The retinal oxidative damage inhibitors of the present invention have anexcellent antioxidation action and are therefore effective toprophylaxis and treatment for degenerative disease of the retina causedby aging, such as aging macular degeneration and diabetic retinopathy.

Lipoxygenase inhibitors, 20-hydroeicosatetraenoic acid (20-HETE)synthase inhibitors and therapeutic agents for kidney diseases,cerebrovascular or circulatory diseases, or cerebral infarction of thepresent invention are not specifically limited as far as they containthe antioxidants containing one or more phenylazole compounds having theantioxidation action or pharmaceutically acceptable salts thereof of thepresent invention as the active ingredient, and the administration mode,the dosage form and the dose may be the same as those in case of theantioxidants. They can contain the same components for preparation,carriers and adjuvants as those in case of the antioxidants and mayfurther contain excipients, disintegrators, binders and one or moreretinal oxidative damage inhibitors which do not react with the activeingredients, and also may contain components having other drug potency.The dosage form may be the same as those in case of the antioxidants.

The phenylazole compounds of the present invention will now be describedin detail by way of examples, but the technical scope of the presentinvention is not limited to these examples.

EXAMPLE 1 Step 1 Production of1-acetyl-4-(4-imidazol-1-ylphenyl)-piperazine

To a reaction solution prepared by dissolving 20 g of1-acetyl-4-(4-bromophenyl)-piperazine and 7.9 g of imidazole in 120 mlof xylene, 16.9 g of 1,10-phenanthroline, 1.4 g of1,5-diphenyl-1,4-pentadien-3-one, 28.9 g of cesium carbonate and 1.8 gof a copper (I) trifluoromethanesulfonate benzene complex, as acatalyst, were added at room temperature, followed by heating at refluxin an argon gas flow at 125° C. for 24 hours. After the completion ofthe reaction, the reaction solution was mixed with 300 ml of an aqueousammonium solution and then extracted with chloroform. The organic layerwas washed with saturated saline and then dried over anhydrous magnesiumsulfate. After removing magnesium sulfate by filtration andconcentrating under reduced pressure, the residue was subjected tosilica gel column chromatography (chloroform:ethylacetate=3:1→chloroform:methanol=20:1) to obtain 15.2 g of the objective1-acetyl-4-(4-imidazol-1-ylphenyl)-piperazine (melting point: 181-182°C.).

Production of 1-(4-imidazol-1-ylphenyl)-piperazine

To 15.2 g of 1-acetyl-4-(4-imidazol-1-ylphenyl)-piperazine, 100 ml ofconcentrated hydrochloric acid was added, followed by heating at refluxfor 3 hours. After the completion of the reaction, the reaction solutionwas cooled and then neutralized with an aqueous 1N sodium hydroxidesolution, thereby to precipitate a crystal. The resulting crystal wasfiltrated, washed with a small amount of water and then dried to obtain12 g of the objective 1-(4-imidazol-1-ylphenyl)-piperazine (meltingpoint: 177-180° C.).

Production of4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)piperazine

0.7 g of 1-(4-imidazol-1-ylphenyl)-piperazine and 0.7 g of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde were dissolvedin 20 ml of methylene chloride and 1 ml of acetic acid as a catalyst wasadded, followed by stirring at room temperature for 30 minutes. To theresulting reaction solution, 1.2 g of sodium triacetoxyborohydride wasadded, followed by stirring at room temperature for 30 minutes. Afterthe completion of the reaction, the reaction solution was poured intowater, neutralized with an aqueous saturated sodium hydrogen carbonatesolution and then extracted with chloroform. The organic layer waswashed with saturated saline and then dried over anhydrous magnesiumsulfate. After removing magnesium sulfate by filtration andconcentrating under reduced pressure, 1.3 g of the objective product wasobtained.

EXAMPLE 2 Step 2 Production of4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)piperazine

To 1.3 g of4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)piperazine,30 ml of ethanol was added and 4.4 g of stannous chloride-dihydrate and15 ml of concentrated hydrochloric acid were added, followed by heatingat reflux for 6 hours. The reaction solution was poured into water,neutralized with a 1N sodium hydroxide solution and then extracted withchloroform. The organic layer was washed with saturated saline and thendried over anhydrous magnesium sulfate. After removing magnesium sulfateby filtration and concentrating under reduced pressure, the residue wassubjected to silica gel column chromatography (chloroform:methanol=30:1)to obtain 0.5 g of the objective product (melting point: 165-167° C.).

EXAMPLE 3 Step 1 Production of(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-[4-(4-imidazol-1-ylphenyl)-piperazin-1-yl]carboxamide

To 0.43 g of 1-(4-imidazol-1-ylphenyl)-piperazine and 0.5 g of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid, 0.44 gof 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.31 gof 1-hydroxybenzotriazole hydrochloride and 0.23 g of triethylamine wereadded, followed by stirring at room temperature for 24 hours. Thereaction solution was poured into water and the precipitated crystal wasremoved by filtration and washed with water and ether, and then theresulting crystal was dried to obtain 0.88 g of the objective compound.

EXAMPLE 4 Step 2 Production of(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-[4-(4-imidazol-1-ylphenyl)-piperazin-1-yl]carboxamide

In an autoclave, 0.88 g of(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-[4-(4-imidazol-1-ylphenyl)-piperazin-1-yl]carboxamideand 0.5 g of 10% palladium carbon, 10 ml of ethanol and 5 ml of aceticacid were added, followed by stirring overnight under a hydrogenpressure of 10 kg/cm². The reaction solution was poured into water,neutralized with a 1N sodium hydroxide solution and then extracted withchloroform. The organic layer was washed with saturated saline and thendried over anhydrous magnesium sulfate. After removing magnesium sulfateby filtration and concentrating under reduced pressure, the residue wassubjected to silica gel column chromatography (chloroform:methanol=10:1)to obtain 0.56 g of the objective product (melting point: 189-191° C.).

A 3-imidazole compound could be synthesized by the same process.

EXAMPLE 5 Step 1 Production of1-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-dimethylaminopropenone

5.7 g of 1-acetyl-4-(4-acetylphenyl)-piperazine and 24 ml ofdimethylaminoacetaldehydehyde dimethylacetal were dissolved in 25 ml ofxylene, followed by heating at reflux for 18 hours while removingmethanol. After the completion of the reaction, the reaction solutionwas cooled, thereby to precipitate a crystal, which was washed withether-hexane (=10:1) to obtain 6.3 g of the objective1-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-dimethylaminopropenone.

Production of 1-acetyl-4-(4-1H-pyrazol-5-ylphenyl)-piperazine

6.3 g of 1-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-dimethylaminopropenoneand 1.6 g of hydrazine hydrate were dissolved in 50 ml of ethanol and0.3 g of p-toluenesulfonic acid as a catalyst was added, followed byheating at reflux for one hour. After the completion of the reaction,the reaction solution was cooled, thereby to precipitate a crystal,which was washed with ether to obtain 5.1 g of the objective1-acetyl-4-(4-1H-pyrazol-5-ylphenyl)-piperazine (melting point: 257-259°C.).

Production of 1-(4-1H-pyrazol-5-ylphenyl)-piperazine

To 5.1 g of 1-acetyl-4-(4-1H-pyrazol-5-ylphenyl)-piperazine, 60 ml ofconcentrated hydrochloric acid were added, followed by heating at refluxfor 3 hours. After the completion of the reaction, the reaction solutionwas cooled and then neutralized with an aqueous 1N sodium hydroxidesolution, thereby to precipitate a crystal. The resulting crystal wasfiltered, washed with a small amount of water and then dried to obtain4.3 g of the objective 1-(4-1H-pyrazol-5-ylphenyl)-piperazine (meltingpoint: 290° C. or higher).

Production of(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-(4-(4-1H-pyrazol-5-ylphenyl)-piperazin-1-yl]carboxamide

To 0.38 g of 1-(4-1H-pyrazol-5-ylphenyl)-piperazine and 0.4 g of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid, 0.35 gof 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.25 gof 1-hydroxybenzotriazole hydrochloride and 0.19 g of triethylamine wereadded, followed by stirring at room temperature for 24 hours. Thereaction solution was poured into water and the precipitated crystal wasremoved by filtration and washed with water, and then the resultingcrystal was dried to obtain 0.65 g of the objective compound.

EXAMPLE 6 Step 2 Production of(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-[4-(4-1H-pyrazol-5-ylphenyl)-piperazin-1-yl]carboxamide

In an autoclave, to 0.65 g of(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-[4-(4-1H-pyrazole-phenyl)-piperazin-1-yl]carboxamideand 0.2 g of 10% palladium carbon, 5 ml of ethanol and 5 ml of aceticacid were added, followed by stirring under a hydrogen pressure of 10kg/cm² for 2 days. The reaction solution was poured into water,neutralized with a 1N sodium hydroxide solution and then extracted withchloroform. The organic layer was washed with saturated saline and thendried over anhydrous magnesium sulfate. After removing magnesium sulfateby filtration and concentrating under reduced pressure, the residue wassubjected to silica gel column chromatography (chloroform:methanol=10:1)to obtain 0.25 g of the objective product (melting point: 128-130° C.).

3-1H-pyrazole compound could be synthesized by the same process.

EXAMPLE 7 Step 1 Production of1-acetyl-4-(4-imidazol-1-ylphenyl)-4-hydroxypiperidine

To a reaction solution prepared by suspending 3 g of1-acetyl-4-(4-bromophenyl)-4-hydroxypiperidine and 1.1 g of imidazole in18 ml of xylene, 2.4 g of 1,10-phenanthroline, 0.2 g of1,5-diphenyl-1,4-pentadien-3-one, 4.3 g of cesium carbonate and 0.3 g ofa copper (I) trifluoromethanesulfonate benzene complex, as a catalyst,were added at room temperature, followed by heating at reflux in anargon gas flow at 125° C. for 24 hours. After the completion of thereaction, the reaction solution was mixed with 50 ml of an aqueousammonium chloride solution and then extracted with chloroform. Theorganic layer was washed with saturated saline and then dried overanhydrous magnesium sulfate. After removing magnesium sulfate byfiltration and concentrating under reduced pressure, the residue wassubjected to silica gel column chromatography (chloroform:ethylacetate=3:1→chloroform:methanol=20:1) to obtain 2.5 g of the objective1-acetyl-4-(4-imidazol-1-yl-phenyl)-4-hydroxypiperidine.

Production of 4-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine

To 2.5 g of 1-acetyl-4-(4-imidazol-1-ylphenyl)-4-hydroxypiperidine, 30ml of concentrated hydrochloric acid was added, followed by heating atreflux for 4 hours. After the completion of the reaction, the reactionsolution was cooled, neutralized with an aqueous 1N sodium hydroxidesolution and then extracted with chloroform. The organic layer waswashed with saturated saline and then dried over dried over anhydrousmagnesium sulfate. After removing magnesium sulfate by filtration andconcentrating under reduced pressure, the resulting crystal was washedwith hexane and then dried to obtain 1.5 g of the objective4-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine (mp: 150-153° C.).

EXAMPLE 8 Step 2 Production of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-trifluoromethanesulfonate

6.7 g of trifluoromethanesulfonic acid anhydride was dissolved in 50 mlof dichloromethane, followed by cooling to 0° C. In the solution, asolution prepared by dissolving 5.0 g of2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran in 50 ml ofdichloromethane and 2.4 g of triethylamine were added dropwise over 30minutes. After the dropwise addition and stirring at 0° C. for one hour,the temperature was raised to room temperature, followed by stirring for1.5 hours. After the reaction, the reaction solution was washed withwater and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was subjected tosilica gel column chromatography (chloroform:methanol=100:1) to obtain7.3 g of the objective product.

EXAMPLE 9 Step 2 Production of4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine

0.7 g of 4-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine and 1.2 gof2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-trifluoromethanesulfonatewere dissolved in 30 ml of acetonitrile and 0.35 g of sodium carbonatewas added, followed by heating at reflux for 24 hours. After thecompletion of the reaction, the reaction solution was poured into waterand then extracted with chloroform. The organic layer was washed withsaturated saline and then dried over anhydrous magnesium sulfate. Afterremoving magnesium sulfate by filtration and concentrating under reducedpressure, 1.2 g of the objective product was obtained.

EXAMPLE 10 Step 3 Production of4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine

To 1.2 g of4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine,30 ml of ethanol was added and 3.6 g of stannous chloride-dihydrate and15 ml of concentrated hydrochloric acid were added, followed by heatingat reflux for 8 hours. The reaction solution was poured into water,neutralized with a 1N sodium hydroxide solution and then extracted withchloroform. The organic layer was washed with saturated saline and thendried over anhydrous magnesium sulfate. After removing magnesium sulfateby filtration and concentrating under reduced pressure, the residue wassubjected to silica gel column chromatography (chloroform:methanol=20:1)to obtain 0.93 g of the objective product (mp: 161-163° C.).

EXAMPLE 11 Production of4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)piperidine

In an autoclave, to 0.45 g of4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridineand 0.1 g of 10% palladium carbon, 5 ml of ethanol and 5 ml of aceticacid were added, followed by stirring at 50° C. under a hydrogenpressure of 10 kg/cm² for 7 hours. The reaction solution was poured intowater, neutralized with 1N sodium hydroxide solution and then extractedwith chloroform. The organic layer was washed with saturated saline andthen dried over anhydrous magnesium sulfate. After removing magnesiumsulfate by filtration and concentrating under reduced pressure, theresulting crystal was washed with hexane and then dried to obtain 0.39 gof the objective product (mp: 170-172° C.).

A 3-imidazole compound can be synthesized by the same process. Also anamide type compound can be synthesized by the same process.

EXAMPLE 12 Step 1: Production of 4-(±)-(5-nitro-2,4,6,7

-tetramethyldihydrobenzofuran-2-ylmethyl)aminophenyl-1-imidazole

1.7 g of 1-(4-aminophenyl)imidazole and 1.09 g of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde were dissolvedin 53 ml of methylene chloride and 0.8 ml of acetic acid was added,followed by stirring at room temperature for 10 minutes. To theresulting reaction solution, 2.91 g of sodium triacetoxyborohydride wasadded, followed by stirring overnight at room temperature. After thecompletion of the reaction, the reaction solution was poured into water,neutralized with an aqueous sodium hydroxide solution and then extractedwith chloroform. The organic layer was washed with saturated saline anddried over anhydrous magnesium sulfate, and then the solvent wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform:methanol=100:3) to obtain 1.2 g ofthe objective product.

Step 2: Production of4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)aminophenyl-1-imidazole

To 0.93 g of4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)aminophenylimidazoleand 0.5 g of 20% palladium hydroxide on carbon, 10 ml of acetic acid wasadded, followed by stirring overnight at 50° C. under a hydrogenpressure of 10 Kg/cm². The reaction solution was filtered through celiteand the filtrate was concentrated under reduced pressure, and then theresidue was purified by silica gel column chromatography (chloroformmethanol=20:1) to obtain 0.57 g of the objective product (refractiveindex nD20.4 1.5693)

EXAMPLE 13 Step 1 Production of5-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)aminophenyl)pyrazole

0.77 g of 5-(4-aminophenyl)pyrazole and 1.00 g of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde were dissolvedin 33 ml of methylene chloride and 0.5 ml of acetic acid was added,followed by stirring at room temperature for 30 minutes. To theresulting reaction solution, 1.70 g of sodium triacetoxyborohydride wasadded, followed by stirring at room temperature for 20 hours. After thecompletion of the reaction, the reaction solution was poured into water,neutralized with an aqueous sodium hydroxide solution and then extractedwith chloroform. The organic layer was washed with hydrochloric acidwater, neutralized with an aqueous sodium hydroxide solution, and thenthe organic layer was washed with saturated saline and dried overanhydrous magnesium sulfate. The solvent was concentrated under reducedpressure to obtain 1.5 g of the objective product.

Step 2: Production of3(5)-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)aminophenyl)-1-(tetrahydropyran-2-yl)pyrazole

0.50 g of5-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)aminophenyl)pyrazoleand 0.01 g of p-toluenesulfonic acid hydrate were dissolved in 2 ml ofethyl acetate and then heated to 50° C. In the solution, a solutionprepared by dissolving 0.13 g of 3,4-dihydro-2H pyran in 2 ml of ethylacetate was added dropwise over 30 minutes, followed by stirring at 55°C. for 10 hours. The reaction solution was cooled, washed with 2 ml of3N ammonia water and then washed until the pH of the organic layerreaches 7. The organic layer was dried over anhydrous magnesium sulfateand the solvent was distilled off, and then residue was purified bysilica gel column chromatography (chloroform:methanol=50:1) to obtain0.60 g of the objective product.

Step 3: Production of3(5)-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)methylaminophenyl)-1-(tetrahydropyran-2-yl)pyrazole

0.23 g of3(5)-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)aminophenyl)-1-(tetrahydropyran-2-yl)pyrazole,1 m of methyl iodide and 0.08 g of potassium carbonate were dissolved in5 ml of acetonitrile, followed by heating at reflux for 3 hours. Afterthe concentration, addition of chloroform and filtration, the filtratewas concentrated, the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:2) to obtain 0.14 g of theobjective product.

Step 4: Production of5-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)methylaminophenyl)pyrazole

0.32 g of3(5)-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)methylaminophenyl)-1-(tetrahydropyran-2-yl)pyrazolewas dissolved in 30 ml of dry methylene chloride, followed by cooling to5° C. A hydrogen chloride gas was bubbled into the solution for 5minutes, followed by stirring at room temperature for 6 hours andfurther standing for 11 hours. The reaction solution was neutralizedwith an aqueous sodium hydroxide solution, extracted with chloroform,washed with saturated saline and dried over anhydrous magnesium sulfate,and then the solvent was distilled off. The residue was purified bysilica gel column chromatography (chloroform:methanol=50:1) to obtain0.26 g of the objective product.

Step 5: Production of5-(4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)methylaminophenyl)pyrazole

To 0.26 g of5-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)methylaminophenyl)pyrazole,10 ml of ethanol was added and 0.43 g of stannous chloride-dihydrate and3 ml of concentrated hydrochloric acid were added, followed by heatingat reflux for 2 hours. The reaction solution was poured into water,neutralized with a sodium hydroxide solution and then extracted withchloroform. The organic layer was washed with saturated saline, driedover anhydrous magnesium sulfate and then distilled off under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=20:1) to obtain 0.22 g of the objective product(melting point: 113-117° C.)

EXAMPLE 14 Step 1: Production of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-trifluoromethanesulfonate

6.7 g of trifluoromethanesulfonic acid anhydride was dissolved in 50 mlof dichloromethane, followed by cooling to 0° C. In the solution, asolution prepared by dissolving 5.0 g of2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran and 2.4 g oftriethylamine in 50 ml of dichloromethane was added dropwise over 30minutes. After the dropwise addition and stirring at 0° C. for one hour,the temperature was raised to room temperature, followed by stirring for1.5 hours. After the reaction, the reaction solution was washed withwater and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=100:1) to obtain7.3 g of the objective product.

Step 2: Production of4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethoxy)-phenyl-1-imidazole

0.25 g of 4-imidazol-1-yl-phenol was dissolved in 5 ml of dimethylformamide and 0.06 g of 60% sodium hydride was added under stirring.After stirring at room temperature for one hour, a solution prepared bydissolving 0.5 g of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-trifluoromethanesulfonatein 5 ml of DMF was added, followed by stirring at room temperature forone hour. After the reaction, the reaction solution was washed withwater and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was allowed tostand for 4 hours and 10 ml of water was added, and then theprecipitated filtered and dried with heating to obtain 0.3 g of theobjective product.

Step 3: Production of4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethoxy)-phenyl-1-imidazole

To 0.3 g of4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethoxy)-phenyl-1-imidazole,10 ml of ethanol was added and 0.5 g of stannous chloride-dihydrate and3 ml of concentrated hydrochloric acid were added, followed by heatingat reflux for 2 hours. The reaction solution was poured into water,neutralized with a 1N sodium hydroxide solution and then extracted withchloroform. The organic layer was washed with saturated saline, driedover anhydrous magnesium sulfate and then distilled off under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=50:1) to obtain 0.2 g of the objective product(melting point: 129-131° C.)

EXAMPLE 154-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethylamino)-phenyl-5-1H-pyrazole(compoundB-2-5-1) was separated using a column for separation of an opticalisomer CHIRALCEL OD (DAICEL CHEMICAL INDUSTRIES, LTD.) to obtain afraction 1 effused first and a fraction 2 effused later. Each fractionwas recrystallized from ethanol-water. A hydrochloride was prepared by aconventional process.

Fraction 1 retention time: 13.7 min

(−)-(compound B-2-5-1) mp [107-110]

[α]_(D)-16.6° (C 1.01, EtOH)

HPLC>99.9% ee

2HCl salt melting point: 183-187° C.

Fraction 2 retention time: 27 min

(+)-(compound B-2-5-1) mp [105-108]

[α]_(D)+16.9° (C 1.00, EtOH)

HPLC 99.8% ee

2HCl salt melting point: 184-188° C.

HPLC conditions column CHIRALCEL OD (4.6×250 mm)

Mobile phase n-hexane:i-propanol:diethylamine 600:400:1

Flow rate: 1.0 ml/min

UV: 254 nm

Column temperature: 40° C.

EXAMPLE 16 Step 1: Production of(±)-2-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-2,3,4,9-tetrahydro-1H-beta-carboline

2.0 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde, 1.52 gof 2,3,4,9-tetrahydro-1H-beta-carboline, 50 ml of methylene chloride,0.8 ml of acetic acid and 2.04 g of sodium triacetoxyborohydride wereadded, followed by stirring overnight at room temperature. The mixturewas poured into ice-water and an aqueous sodium hydroxide solution wasadded. The reaction solution was extracted with chloroform, washed withsaturated saline and dried over anhydrous magnesium sulfate and, afterthe solvent was distilled off under reduced pressure, the residue waspurified by silica gel column chromatography (chloroform:ethylacetate=50:1) to obtain 1.49 g of the objective product.

Step 2: Production of(±)-2-(5-amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethyl)-2,3,4,9-tetrahydro-1H-beta-carboline

1.49 g of(±)-2-(5-nitro-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethyl)-2,3,4,9-tetrahydro-1H-beta-carboline,2.49 g of stannous chloride, 11 ml of hydrochloric acid and 25 ml ofethanol were added and, after heating at reflux for 6.5 hours, themixture was poured into ice-water and an aqueous sodium hydroxidesolution was added. The reaction solution was extracted with chloroform,washed with saturated saline and dried over anhydrous magnesium sulfateand, after the solvent was distilled off under reduced pressure, theresidue was purified by silica gel column chromatography(chloroform:methanol=100:3) to obtain 1.07 g of the objective product(melting point: 150-153° C.)

EXAMPLE 17 Step 1: Production of(±)-(1,3,4,9-tetrahydro-beta-carboline-2-yl)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)methanone

0.5 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid,20 ml of methylene chloride and 0.27 g of thionyl chloride were added,followed by heating at reflux for 2 hours. After returning thetemperature to room temperature, the solvent was distilled off to obtain2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride.To 0.33 g of 2,3,4,9-tetrahydro-1H-beta-carboline, 0.23 g oftriethylamine and 15 ml of DMF, a solution prepared by dissolving2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride inDMF was added, followed by stirring overnight at room temperature. Themixture was poured into ice-water and a crystal was collected byfiltration. The crystal was dissolved in chloroform, washed withsaturated saline and dried over anhydrous magnesium sulfate and, afterthe solvent was distilled off under reduced pressure, the residue waspurified by silica gel column chromatography (chloroform:methanol=100:1)to obtain 0.54 g of the objective product.

Step 2: Production of(±)-(5-amino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl)-(1,3,4,9-tetrahydro-beta-carboline-2-yl)-methanone

0.54 g of(±)-(1,3,4,9-tetrahydro-beta-carboline-2-yl)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)methanone,1.86 g of zinc, 0.19 g of calcium chloride dehydrate and 30 ml ofethanol were added, followed by heating at reflux overnight. Theinsoluble matter was filtered through celite and the solvent wasdistilled off. The reaction solution was mixed with water, extractedwith chloroform, washed with saturated saline and dried over anhydrousmagnesium sulfate and, after the solvent was distilled off under reducedpressure, the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=50:1) to obtain 0.19 g of the objectiveproduct (melting point: 129-133° C.)

REFERENCE EXAMPLE 1

Production of 2,3,5-trimethylphenyl-2-methyl-2-propenylether

91.1 g of 2,3,5-trimethylphenol, 65.3 g of 3-chloro-2-methylpropene and99 g of potassium carbonate were added to 700 ml of DMF, followed bystirring at 80° C. for 3 hours. After cooling, the reaction solution waspoured into ice-water and then extracted with ethyl acetate. Thesolution was washed in turn with water and saturated saline and driedover anhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure and the residue was purified by silica gel columnchromatography (benzene:hexane=1:1) to obtain 102 g of the objectiveproduct.

REFERENCE EXAMPLE 2 Production of2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol

26.6 g of 2,3,5-trimethylphenyl-2-methyl-2-propenylether was dissolvedin 131 ml of diethylaniline, followed by stirring under an argonatmosphere at 200° C. for 2 hours. After cooling, the solution waspoured into 6N-hydrochloric acid and then extracted with ether. Thesolution was washed in turn with dilute hydrochloric acid, water andsaturated saline and dried over anhydrous magnesium sulfate and, afterthe solvent was distilled of under reduced pressure, the residue waspurified by silica gel column chromatography (benzene:hexane=1:1) toobtain 21.4 g of the objective product.

REFERENCE EXAMPLE 3 Production of2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran

31.86 g of 2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol was dissolvedin 600 ml of methylene chloride and 47.5 g of methchloroperbenzoic acidwas gradually charged while maintaining at 0° C. After stirring at 0° C.for 2 hours, the solution was poured into an aqueous sodium hydrogencarbonate. The organic layer was extracted with chloroform, washed withan aqueous saturated sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate and, after the solvent was distilled off,the residue was purified by silica gel column chromatography(chloroform) to obtain 17 g of the objective product.

REFERENCE EXAMPLE 4 Production of2-hydroxymethyl-2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran

2.3 g of 2-hydroxymethyl-2,4,6,7-tetramethyldihydrobenzofuran wasdissolved in 30 ml of anhydrous acetic acid and 1.9 ml of nitric acidwas added dropwise while stirring at 0° C. After stirring at 0° C. forone hour, the solution was poured into ice-water, followed by stirringat room temperature for one hour. The reaction solution was extractedwith ether, washed with saturated saline and dried over anhydrousmagnesium sulfate and, after the solvent was distilled off under reducedpressure, the residue was purified by silica gel column chromatography(chloroform) to obtain 1.34 g of the objective product.

REFERENCE EXAMPLE 5 Production of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde

Under an argon atmosphere, 0.57 ml of oxalic acid dichloride wasdissolved in 12 ml of methylene chloride, followed by cooling to −78° C.To this solution, a solution prepared by dissolving 1.1 ml of DMSO in 2ml of methylene chloride was added dropwise at −65 C or lower, followedby stirring for 10 minutes. Furthermore, a solution prepared bydissolving 1.34 g of2-hydroxymethyl-2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran in 4 ml ofmethylene chloride was added dropwise, followed by stirring at −78° C.for 3 hours. After the completion of the reaction, 4.2 ml oftriethylamine was added dropwise and the reaction solution was heated toroom temperature and then 1N-hydrochloric acid was added. The organiclayer was extracted with chloroform, washed with saturated saline anddried over anhydrous magnesium sulfate, and then solvent was distilledoff under reduced pressure and the residue was purified by silica gelcolumn chromatography (chloroform) to obtain 0.86 g of the objectiveproduct.

REFERENCE EXAMPLE 6 Production of2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid

2.39 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde and 31g of 2-methyl-2-butene were dissolved in 190 ml of t-butanol and asolution prepared by dissolving 7.77 g of sodium chlorite and 10.1 g ofsodium dihydrogen phospahte dehydrate in 78 ml of water was addeddropwise under ice cooling, followed by stirring at room temperature for2 hours. After 2-methyl-2-butene and t-butanol were distilled off underreduced pressure, water was added and the reaction solution wasextracted with ether. The solution was washed with saturated saline anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure and the residue was crystallizedfrom ether-hexane to obtain 1.20 g of the objective product.

REFERENCE EXAMPLE 7 Production of6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman-4-one

To the reaction solution prepared by dissolving 66.5 g of5-nitro-2-hydroxy-3,4,6-trimethylacetophenone and 78.8 g ofmethoxyacetone in 500 ml of toluene, 6.4 g of pyrrolidine was added atroom temperature, followed by stirring at room temperature for 24 hoursand further heating at reflux for 3 hours. The reaction solution wasdistilled off under reduced pressure and the residue was subjected tosilica gel column chromatography (hexane:ethyl acetate=7:1→3:1) toobtain 29.2 g of the objective product.

REFERENCE EXAMPLE 8 Production of6-nitro-4-hydroxy-2-methoxymethyl-2,5,7,8-tetramethylchroman

To 10 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman-4-one, 100ml of methanol was added and 1.3 g of sodium borohydride was added at 0°C., followed by stirring at 0° C. for one hour. The reaction solutionwas poured into water and then extracted with ethyl acetate. The organiclayer was washed with saturated saline and then dried over anhydrousmagnesium sulfate. After removing magnesium sulfate by filtration andconcentrating under reduced pressure, 10.1 g of the objective compoundwas obtained.

REFERENCE EXAMPLE 9 Production of6-nitro-2-methoxymethyl-2,5,7,8-tetramethyl (2H) chromene

To 10.1 g of6-nitro-4-hydroxy-2-methoxymethyl-2,5,7,8-tetramethylchroman, 200 ml ofbenzene was added and 1.0 g of p-toluenesulfonic acid was added,followed by heating at reflux for 2 hours using a Dean-Stark apparatus.The reaction solution was poured into water and then extracted withethyl acetate. The organic layer was washed with an aqueous saturatedsodium hydrogen carbonate solution, washed with saturated saline andthen dried over anhydrous magnesium sulfate. After removing magnesiumsulfate by filtration and concentrating under reduced pressure, 9.4 g ofthe objective oily compound was obtained.

REFERENCE EXAMPLE 10 Production of6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman

9.4 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethyl (2H) chromene wasdissolved in 100 ml of ethanol and 1.0 g of a 10% palladium carboncatalyst was added and, after sealing hydrogen, the catalytichydrogenation reaction was carried out at room temperature under normalpressure for 24 hours. After the completion of the reaction, thereaction solution was filtered and then concentrated under reducedpressure to obtain 9.5 g of the objective oily compound.

REFERENCE EXAMPLE 11 Production of6-nitro-2-hydroxymethyl-2,5,7,8-tetramethylchroman

9.5 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman wasdissolved in 80 ml of methylene chloride and 31.4 ml of a 1M borontribromidemethylene chloride solution was added under a nitrogen gasflow at 0° C., followed by stirring at 0° C. for 3 hours. After thecompletion of the reaction, the reaction solution was poured into waterand then extracted with chloroform. The organic layer was washed withsaturated saline and then dried over anhydrous magnesium sulfate. Afterremoving magnesium sulfate by filtration and concentrating under reducedpressure, the residue was subjected to silica gel column chromatography(hexane:ethyl acetate=2:1) to obtain 4.5 g of the objective product.

REFERENCE EXAMPLE 12 Production of6-nitro-2-formyl-2,5,7,8-tetramethylchroman

Under a nitrogen flow at −60° C., 1.6 ml of oxalic acid dichloride wasdissolved in 40 ml of methylene chloride and 3.1 ml of DMSO was addeddropwise at −60° C., followed by stirring for 5 minutes. A solutionprepared by dissolving 3.9 g of6-nitro-2-hydroxymethyl-2,5,7,8-tetramethylchroman in 10 ml of methylenechloride was added dropwise under a nitrogen gas flow at −60° C.,followed by stirring at −60° C. for 30 minutes. 12 ml of triethylaminewas added at −60° C. and the temperature was gradually raised to roomtemperature, thereby to complete the reaction. After the completion ofthe reaction, the reaction solution was poured into water and thenextracted with chloroform. The organic layer was washed with saturatedsaline and then dried over anhydrous magnesium sulfate. After removingmagnesium sulfate by filtration and concentrating under reducedpressure, the residue was subjected to silica gel column chromatography(hexane:ethyl acetate=2:1) to obtain 3.4 g of the objective product as acrystal.

REFERENCE EXAMPLE 13 Production of6-nitro-2,5,7,8-tetramethylchroman-2-carboxylic acid

2.3 g of 6-nitro-2-formyl-2,5,7,8-tetramethylchroman was dissolved in150 ml of t-butanol and 23 g of 2-methyl-2-butene was added at roomtemperature. An aqueous solution prepared by dissolving 5.8 g of sodiumchlorite and 7.6 g of sodium dihydrogen phosphate dehydrate in 60 ml ofwater was added dropwise at room temperature, followed by stirring atroom temperature for 2 hours. After the completion of the reaction, thereaction solution was poured into water and then extracted with ether.The organic layer was partitioned with an aqueous 5% sodium hydrogencarbonate solution and the ether layer was discarded. The pH of theaqueous layer was adjusted to 4 with 10% hydrochloric acid, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline and then dried over anhydrous magnesium sulfate. Afterremoving magnesium sulfate by filtration and concentrating under reducedpressure, the resulting crystal was washed with hexane to obtain 1.6 gof the objective product.

Specific examples of the compounds of the present invention are shown inTables 1 to 29. With respect to the compounds in which “& NMR” isdescribed in the column of physical constant in the tables, NMR datawere described in the last of the tables. “decomp.” in the tablesindicates decomposition. Abbreviations and symbols in the tables are asfollows:

Me: methyl, Et: ethyl, Bu: butyl, Ph: phenyl, al: 1-imidazolyl, and a2:1H-pyrazol-5-yl. The numeral attached to a1 and a2 in the column Aindicates the position of a phenyl group to be attached.

TABLE 1

Compound Physical constant No. A D Z [ ] m.p. ° C. B-1-1 4-a1 CO h1[189-191] B-1-2 4-a1 CH₂ h1 [165-167] B-1-3 4-a1 CO h2 [110-115] B-1-44-a1 CH₂ h2 [65-67] B-1-5 4-a1 CO h3 [249-251] B-1-6 4-a1 CH₂ h3[219-221] B-1-7 4-a1 CO h4 [218-220] B-1-8 4-a1 CH₂ h4 [94-98] B-1-94-a1 CO h5 [288-290] B-1-10 4-a1 CH₂ h5 [68-70] B-1-11 4-a1 CO h6 & NMRB-1-12 4-a1 CH₂ h6 n_(D) ^(20.7)1.5527 B-1-13 4-a1 CO h7 & NMR B-1-144-a1 CH₂ h7 [176-178] B-1-15 4-a1 CO h8 [243-246] B-1-16 4-a1 CH₂ h8[201-203] B-1-17 3-a1 CO h1 [90-93] B-1-18 3-a1 CH₂ h1 [58-60] B-1-193-a1 CO h2 [90-93] B-1-20 3-a1 CH₂ h2 [146-149] B-1-21 3-a1 CO h3 B-1-223-a1 CH₂ h3 [148-151] B-1-23 3-a1 CO h4 B-1-24 3-a1 CH₂ h4 B-1-25 3-a1CO h5 B-1-26 3-a1 CH₂ h5 [197-198] B-1-27 3-a1 CO h6 B-1-28 3-a1 CH₂ h6& NMR B-1-29 3-a1 CO h7 B-1-30 3-a1 CH₂ h7 B-1-31 3-a1 CO h8 B-1-32 3-a1CH₂ h8 B-1-33 4-a2 CO h1 [128-130] B-1-34 4-a2 CH₂ h1 [205-207] B-1-354-a2 CO h2 [115-120] B-1-36 4-a2 CH₂ h2 [110-115] B-1-37 4-a2 CO h3 &NMR B-1-38 4-a2 CH₂ h3 B-1-39 4-a2 CO h4 & NMR B-1-40 4-a2 CH₂ h4 B-1-414-a2 CO h5 B-1-42 4-a2 CH₂ h5 B-1-43 4-a2 CO h6 B-1-44 4-a2 CH₂ h6B-1-45 4-a2 CO h7 B-1-46 4-a2 CH₂ h7 B-1-47 4-a2 CO h8 B-1-48 4-a2 CH₂h8 B-1-49 3-a2 CO h1 [120-122] B-1-50 3-a2 CH₂ h1 [94-97] B-1-51 3-a2 COh2 B-1-52 3-a2 CH₂ h2 B-1-53 3-a2 CO h3 [120-122] B-1-54 3-a2 CH₂ h3B-1-55 3-a2 CO h4 B-1-56 3-a2 CH₂ h4 B-1-57 3-a2 CO h5 B-1-58 3-a2 CH₂h5 B-1-59 3-a2 CO h6 B-1-60 3-a2 CH₂ h6 B-1-61 3-a2 CO h7 B-1-62 3-a2CH₂ h7 B-1-63 3-a2 CO h8 B-1-64 3-a2 CH₂ h8

TABLE 2

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-65 4-a1 CO h1B-1-66 4-a1 CH₂ h1 [170-172] B-1-67 4-a1 CO h2 B-1-68 4-a1 CH₂ h2[191-193] B-1-69 4-a1 CO h3 B-1-70 4-a1 CH₂ h3 B-1-71 4-a1 CO h4 B-1-724-a1 CH₂ h4 B-1-73 4-a1 CO h5 B-1-74 4-a1 CH₂ h5 B-1-75 4-a1 CO h6B-1-76 4-a1 CH₂ h6 B-1-77 4-a1 CO h7 B-1-78 4-a1 CH₂ h7 B-1-79 4-a1 COh8 B-1-80 4-a1 CH₂ h8 B-1-81 3-a1 CO h1 B-1-82 3-a1 CH₂ h1 B-1-83 3-a1CO h2 B-1-84 3-a1 CH₂ h2 B-1-85 3-a1 CO h3 B-1-86 3-a1 CH₂ h3 B-1-873-a1 CO h4 B-1-88 3-a1 CH₂ h4 B-1-89 3-a1 CO h5 B-1-90 3-a1 CH₂ h5B-1-91 3-a1 CO h6 B-1-92 3-a1 CH₂ h6 B-1-93 3-a1 CO h7 B-1-94 3-a1 CH₂h7 B-1-95 3-a1 CO h8 B-1-96 3-a1 CH₂ h8 B-1-97 4-a2 CO h1 B-1-98 4-a2CH₂ h1 B-1-99 4-a2 CO h2 B-1-100 4-a2 CH₂ h2 B-1-101 4-a2 CO h3 B-1-1024-a2 CH₂ h3 B-1-103 4-a2 CO h4 B-1-104 4-a2 CH₂ h4 B-1-105 4-a2 CO h5B-1-106 4-a2 CH₂ h5 B-1-107 4-a2 CO h6 B-1-108 4-a2 CH₂ h6 B-1-109 4-a2CO h7 B-1-110 4-a2 CH₂ h7 B-1-111 4-a2 CO h8 B-1-112 4-a2 CH₂ h8 B-1-1133-a2 CO h1 B-1-114 3-a2 CH₂ h1 B-1-115 3-a2 CO h2 B-1-116 3-a2 CH₂ h2B-1-117 3-a2 CO h3 B-1-118 3-a2 CH₂ h3 B-1-119 3-a2 CO h4 B-1-120 3-a2CH₂ h4 B-1-121 3-a2 CO h5 B-1-122 3-a2 CH₂ h5 B-1-123 3-a2 CO h6 B-1-1243-a2 CH₂ h6 B-1-125 3-a2 CO h7 B-1-126 3-a2 CH₂ h7 B-1-127 3-a2 CO h8B-1-128 3-a2 CH₂ h8

TABLE 3

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-129 4-a1 CO h1[85-90] B-1-130 4-a1 CH₂ h1 [60-65] B-1-131 4-a1 CO h2 [206-210] B-1-1324-a1 CH₂ h2 [57-60] B-1-133 4-a1 CO h3 B-1-134 4-a1 CH₂ h3 B-1-135 4-a1CO h4 B-1-136 4-a1 CH₂ h4 B-1-137 4-a1 CO h5 B-1-138 4-a1 CH₂ h5[178-180] B-1-139 4-a1 CO h6 B-1-140 4-a1 CH₂ h6 B-1-141 4-a1 CO h7B-1-142 4-a1 CH₂ h7 B-1-143 4-a1 CO h8 B-1-144 4-a1 CH₂ h8 B-1-145 3-a1CO h1  [95-100] B-1-146 3-a1 CH₂ h1 [70-75] B-1-147 3-a1 CO h2 [80-83]B-1-148 3-a1 CH₂ h2 & NMR B-1-149 3-a1 CO h3 B-1-150 3-a1 CH₂ h3 B-1-1513-a1 CO h4 B-1-152 3-a1 CH₂ h4 B-1-153 3-a1 CO h5 B-1-154 3-a1 CH₂ h5B-1-155 3-a1 CO h6 B-1-156 3-a1 CH₂ h6 B-1-157 3-a1 CO h7 B-1-158 3-a1CH₂ h7 B-1-159 3-a1 CO h8 B-1-160 3-a1 CH₂ h8 B-1-161 4-a2 CO h1 B-1-1624-a2 CH₂ h1 [78-80] B-1-163 4-a2 CO h2 B-1-164 4-a2 CH₂ h2 B-1-165 4-a2CO h3 B-1-166 4-a2 CH₂ h3 B-1-167 4-a2 CO h4 B-1-168 4-a2 CH₂ h4 B-1-1694-a2 CO h5 B-1-170 4-a2 CH₂ h5 B-1-171 4-a2 CO h6 B-1-172 4-a2 CH₂ h6B-1-173 4-a2 CO h7 B-1-174 4-a2 CH₂ h7 B-1-175 4-a2 CO h8 B-1-176 4-a2CH2 h8 B-1-177 3-a2 CO h1 B-1-178 3-a2 CH₂ h1 B-1-179 3-a2 CO h2 B-1-1803-a2 CH₂ h2 B-1-181 3-a2 CO h3 B-1-182 3-a2 CH₂ h3 B-1-183 3-a2 CO h4B-1-184 3-a2 CH₂ h4 B-1-185 3-a2 CO h5 B-1-186 3-a2 CH₂ h5 B-1-187 3-a2CO h6 B-1-188 3-a2 CH₂ h6 B-1-189 3-a2 CO h7 B-1-190 3-a2 CH₂ h7 B-1-1913-a2 CO h8 B-1-192 3-a2 CH₂ h8

TABLE 4

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-193 4-a1 CO h1B-1-194 4-a1 CH₂ h1 [161-163] B-1-195 4-a1 CO h2 B-1-196 4-a1 CH₂ h2[149-151] B-1-197 4-a1 CO h3 B-1-198 4-a1 CH₂ h3 B-1-199 4-a1 CO h4B-1-200 4-a1 CH₂ h4 B-1-201 4-a1 CO h5 B-1-202 4-a1 CH₂ h5 B-1-203 4-a1CO h6 B-1-204 4-a1 CH2 h6 B-1-205 4-a1 CO h7 B-1-206 4-a1 CH₂ h7 B-1-2074-a1 CO h8 B-1-208 4-a1 CH₂ h8 B-1-209 3-a1 CO h1 B-1-210 3-a1 CH₂ h1B-1-211 3-a1 CO h2 B-1-212 3-a1 CH₂ h2 B-1-213 3-a1 CO h3 B-1-214 3-a1CH₂ h3 B-1-215 3-a1 CO h4 B-1-216 3-a1 CH₂ h4 B-1-217 3-a1 CO h5 B-1-2183-a1 CH₂ h5 B-1-219 3-a1 CO h6 B-1-220 3-a1 CH₂ h6 B-1-221 3-a1 CO h7B-1-222 3-a1 CH₂ h7 B-1-223 3-a1 CO h8 B-1-224 3-a1 CH₂ h8 B-1-225 4-a2CO h1 B-1-226 4-a2 CH₂ h1 B-1-227 4-a2 CO h2 B-1-228 4-a2 CH₂ h2 B-1-2294-a2 CO h3 B-1-230 4-a2 CH₂ h3 B-1-231 4-a2 CO h4 B-1-232 4-a2 CH₂ h4B-1-233 4-a2 CO h5 B-1-234 4-a2 CH₂ h5 B-1-235 4-a2 CO h6 B-1-236 4-a2CH₂ h6 B-1-237 4-a2 CO h7 B-1-238 4-a2 CH₂ h7 B-1-239 4-a2 CO h8 B-1-2404-a2 CH₂ h8 B-1-241 3-a2 CO h1 B-1-242 3-a2 CH₂ h1 B-1-243 3-a2 CO h2B-1-244 3-a2 CH₂ h2 B-1-245 3-a2 CO h3 B-1-246 3-a2 CH₂ h3 B-1-247 3-a2CO h4 B-1-248 3-a2 CH₂ h4 B-1-249 3-a2 CO h5 B-1-250 3-a2 CH₂ h5 B-1-2513-a2 CO h6 B-1-252 3-a2 CH₂ h6 B-1-253 3-a2 CO h7 B-1-254 3-a2 CH₂ h7B-1-255 3-a2 CO h8 B-1-256 3-a2 CH₂ h8

TABLE 5

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-257 4-a1 CO h1B-1-258 4-a1 CH₂ h1 B-1-259 4-a1 CO h2 B-1-260 4-a1 CH₂ h2 B-1-261 4-a1CO h3 B-1-262 4-a1 CH₂ h3 [232] (decomp.) B-1-263 4-a1 CO h4 B-1-2644-a1 CH₂ h4 B-1-265 4-a1 CO h5 B-1-266 4-a1 CH₂ h5 B-1-267 4-a1 CO h6B-1-268 4-a1 CH₂ h6 B-1-269 4-a1 CO h7 B-1-270 4-a1 CH₂ h7 B-1-271 4-a1CO h8 B-1-272 4-a1 CH₂ h8 B-1-273 3-a1 CO h1 B-1-274 3-a1 CH₂ h1 B-1-2753-a1 CO h2 B-1-276 3-a1 CH₂ h2 B-1-277 3-a1 CO h3 B-1-278 3-a1 CH₂ h3B-1-279 3-a1 CO h4 B-1-280 3-a1 CH₂ h4 B-1-281 3-a1 CO h5 B-1-282 3-a1CH₂ h5 B-1-283 3-a1 CO h6 B-1-284 3-a1 CH₂ h6 B-1-285 3-a1 CO h7 B-1-2863-a1 CH₂ h7 B-1-287 3-a1 CO h8 B-1-288 3-a1 CH₂ h8 B-1-289 4-a2 CO h1B-1-290 4-a2 CH₂ h1 B-1-291 4-a2 CO h2 B-1-292 4-a2 CH₂ h2 B-1-293 4-a2CO h3 B-1-294 4-a2 CH₂ h3 B-1-295 4-a2 CO h4 B-1-296 4-a2 CH₂ h4 B-1-2974-a2 CO h5 B-1-298 4-a2 CH₂ h5 B-1-299 4-a2 CO h6 B-1-300 4-a2 CH₂ h6B-1-301 4-a2 CO h7 B-1-302 4-a2 CH₂ h7 B-1-303 4-a2 CO h8 B-1-304 4-a2CH₂ h8 B-1-305 3-a2 CO h1 B-1-306 3-a2 CH₂ h1 B-1-307 3-a2 CO h2 B-1-3083-a2 CH₂ h2 B-1-309 3-a2 CO h3 B-1-310 3-a2 CH₂ h3 B-1-311 3-a2 CO h4B-1-312 3-a2 CH₂ h4 B-1-313 3-a2 CO h5 B-1-314 3-a2 CH₂ h5 B-1-315 3-a2CO h6 B-1-316 3-a2 CH₂ h6 B-1-317 3-a2 CO h7 B-1-318 3-a2 CH₂ h7 B-1-3193-a2 CO h8 B-1-320 3-a2 CH₂ h8

TABLE 6

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-321 4-a1 CO h1B-1-322 4-a1 CH₂ h1 B-1-323 4-a1 CO h2 B-1-324 4-a1 CH₂ h2 B-1-325 4-a1CO h3 B-1-326 4-a1 CH₂ h3 & NMR B-1-327 4-a1 CO h4 B-1-328 4-a1 CH₂ h4B-1-329 4-a1 CO h5 B-1-330 4-a1 CH₂ h5 B-1-331 4-a1 CO h6 B-1-332 4-a1CH₂ h6 & NMR B-1-333 4-a1 CO h7 B-1-334 4-a1 CH₂ h7 B-1-335 4-a1 CO h8B-1-336 4-a1 CH₂ h8 B-1-337 3-a1 CO h1 B-1-338 3-a1 CH₂ h1 B-1-339 3-a1CO h2 B-1-340 3-a1 CH₂ h2 B-1-341 3-a1 CO h3 B-1-342 3-a1 CH₂ h3 B-1-3433-a1 CO h4 B-1-344 3-a1 CH₂ h4 B-1-345 3-a1 CO h5 B-1-346 3-a1 CH₂ h5B-1-347 3-a1 CO h6 B-1-348 3-a1 CH₂ h6 B-1-349 3-a1 CO h7 B-1-350 3-a1CH₂ h7 B-1-351 3-a1 CO h8 B-1-352 3-a1 CH₂ h8 B-1-353 4-a2 CO h1 B-1-3544-a2 CH₂ h1 B-1-355 4-a2 CO h2 B-1-356 4-a2 CH₂ h2 B-1-357 4-a2 CO h3B-1-358 4-a2 CH₂ h3 B-1-359 4-a2 CO h4 B-1-360 4-a2 CH₂ h4 B-1-361 4-a2CO h5 B-1-362 4-a2 CH₂ h5 B-1-363 4-a2 CO h6 B-1-364 4-a2 CH₂ h6 B-1-3654-a2 CO h7 B-1-366 4-a2 CH₂ h7 B-1-367 4-a2 CO h8 B-1-368 4-a2 CH₂ h8B-1-369 3-a2 CO h1 B-1-370 3-a2 CH₂ h1 B-1-371 3-a2 CO h2 B-1-372 3-a2CH₂ h2 B-1-373 3-a2 CO h3 B-1-374 3-a2 CH₂ h3 B-1-375 3-a2 CO h4 B-1-3763-a2 CH₂ h4 B-1-377 3-a2 CO h5 B-1-378 3-a2 CH₂ h5 B-1-379 3-a2 CO h6B-1-380 3-a2 CH₂ h6 B-1-381 3-a2 CO h7 B-1-382 3-a2 CH₂ h7 B-1-383 3-a2CO h8 B-1-384 3-a2 CH₂ h8

TABLE 7

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-385 4-a1 CO h1[245] (decomp.) B-1-386 4-a1 CH₂ h1 n_(D) ^(20.6)1.5646 B-1-387 4-a1 COh2 B-1-388 4-a1 CH₂ h2 B-1-389 4-a1 CO h3 B-1-390 4-a1 CH₂ h3 B-1-39l4-a1 CO h4 B-1-392 4-a1 CH₂ h4 B-1-393 4-a1 CO h5 B-1-394 4-a1 CH₂ h5B-1-395 4-a1 CO h6 B-1-396 4-a1 CH₂ h6 n_(D) ^(21.2)1.5329 B-1-397 4-a1CO h7 B-1-398 4-a1 CH₂ h7 B-1-399 4-a1 CO h8 B-1-400 4-a1 CH₂ h8 B-1-4013-a1 CO h1 B-1-402 3-a1 CH₂ h1 B-1-403 3-a1 CO h2 B-1-404 3-a1 CH₂ h2B-1-405 3-a1 CO h3 B-1-406 3-a1 CH₂ h3 B-1-407 3-a1 CO h4 B-1-408 3-a1CH₂ h4 B-1-409 3-a1 CO h5 B-1-410 3-a1 CH₂ h5 B-1-411 3-a1 CO h6 B-1-4123-a1 CH₂ h6 B-1-413 3-a1 CO h7 B-1-414 3-a1 CH₂ h7 B-1-415 3-a1 CO h8B-1-416 3-a1 CH₂ h8 B-1-417 4-a2 CO h1 B-1-418 4-a2 CH₂ h1 B-1-419 4-a2CO h2 B-1-420 4-a2 CH₂ h2 B-1-421 4-a2 CO h3 B-1-422 4-a2 CH₂ h3 B-1-4234-a2 CO h4 B-1-424 4-a2 CH₂ h4 B-1-425 4-a2 CO h5 B-1-426 4-a2 CH₂ h5B-1-427 4-a2 CO h6 B-1-428 4-a2 CH₂ h6 B-1-429 4-a2 CO h7 B-1-430 4-a2CH₂ h7 B-1-431 4-a2 CO h8 B-1-432 4-a2 CH₂ h8 B-1-433 3-a2 CO h1 B-1-4343-a2 CH₂ h1 B-1-435 3-a2 CO h2 B-1-436 3-a2 CH₂ h2 B-1-437 3-a2 CO h3B-1-438 3-a2 CH₂ h3 B-1-439 3-a2 CO h4 B-1-440 3-a2 CH₂ h4 B-1-441 3-a2CO h5 B-1-442 3-a2 CH₂ h5 B-1-443 3-a2 CO h6 B-1-444 3-a2 CH₂ h6 B-1-4453-a2 CO h7 B-1-446 3-a2 CH₂ h7 B-1-447 3-a2 CO h8 B-1-448 3-a2 CH₂ h8

TABLE 8

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-449 4-a1 CO h1B-1-450 4-a1 CH₂ h1 n_(D) ^(20.7)1.5376 B-1-451 4-a1 CO h2 B-1-452 4-a1CH₂ h2 B-1-453 4-a1 CO h3 B-1-454 4-a1 CH₂ h3 B-1-455 4-a1 CO h4 B-1-4564-a1 CH₂ h4 B-1-457 4-a1 CO h5 B-1-458 4-a1 CH₂ h5 B-1-459 4-a1 CO h6B-1-460 4-a1 CH₂ h6 n_(D) ^(20.7)1.5307 B-1-461 4-a1 CO h7 B-1-462 4-a1CH₂ h7 B-1-463 4-a1 CO h8 B-1-464 4-a1 CH₂ h8 B-1-465 3-a1 CO h1 B-1-4663-a1 CH₂ h1 B-1-467 3-a1 CO h2 B-1-468 3-a1 CH₂ h2 B-1-469 3-a1 CO h3B-1-470 3-a1 CH₂ h3 B-1-471 3-a1 CO h4 B-1-472 3-a1 CH₂ h4 B-1-473 3-a1CO h5 B-1-474 3-a1 CH₂ h5 B-1-475 3-a1 CO h6 B-1-476 3-a1 CH₂ h6 B-1-4773-a1 CO h7 B-1-478 3-a1 CH₂ h7 B-1-479 3-a1 CO h8 B-1-480 3-a1 CH₂ h8B-1-481 4-a2 CO h1 B-1-482 4-a2 CH₂ h1 B-1-483 4-a2 CO h2 B-1-484 4-a2CH₂ h2 B-1-485 4-a2 CO h3 B-1-486 4-a2 CH₂ h3 B-1-487 4-a2 CO h4 B-1-4884-a2 CH₂ h4 B-1-489 4-a2 CO h5 B-1-490 4-a2 CH₂ h5 B-1-491 4-a2 CO h6B-1-492 4-a2 CH₂ h6 B-1-493 4-a2 CO h7 B-1-494 4-a2 CH₂ h7 B-1-495 4-a2CO h8 B-1-496 4-a2 CH₂ h8 B-1-497 3-a2 CO h1 B-1-498 3-a2 CH₂ h1 B-1-4993-a2 CO h2 B-1-500 3-a2 CH₂ h2 B-1-501 3-a2 CO h3 B-1-502 3-a2 CH₂ h3B-1-503 3-a2 CO h4 B-1-504 3-a2 CH₂ h4 B-1-505 3-a2 CO h5 B-1-506 3-a2CH₂ h5 B-1-507 3-a2 CO h6 B-1-508 3-a2 CH₂ h6 B-1-509 3-a2 CO h7 B-1-5103-a2 CH₂ h7 B-1-511 3-a2 CO h8 B-1-512 3-a2 CH₂ h8

TABLE 9

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-513 4-a1 CO h1B-1-514 4-a1 CH₂ h1 B-1-515 4-a1 CO h2 B-1-516 4-a1 CH₂ h2 B-1-517 4-a1CO h3 B-1-518 4-a1 CH₂ h3 B-1-519 4-a1 CO h4 B-1-520 4-a1 CH₂ h4 B-1-5214-a1 CO h5 B-1-522 4-a1 CH₂ h5 B-1-523 4-a1 CO h6 B-1-524 4-a1 CH₂ h6B-1-525 4-a1 CO h7 B-1-526 4-a1 CH₂ h7 B-1-527 4-a1 CO h8 B-1-528 4-a1CH₂ h8 B-1-529 3-a1 CO h1 B-1-530 3-a1 CH₂ h1 B-1-531 3-a1 CO h2 B-1-5323-a1 CH₂ h2 B-1-533 3-a1 CO h3 B-1-534 3-a1 CH₂ h3 B-1-535 3-a1 CO h4B-1-536 3-a1 CH₂ h4 B-1-537 3-a1 CO h5 B-1-538 3-a1 CH₂ h5 B-1-539 3-a1CO h6 B-1-540 3-a1 CH₂ h6 B-1-541 3-a1 CO h7 B-1-542 3-a1 CH₂ h7 B-1-5433-a1 CO h8 B-1-544 3-a1 CH₂ h8 B-1-545 4-a2 CO h1 B-1-546 4-a2 CH₂ h1B-1-547 4-a2 CO h2 B-1-548 4-a2 CH₂ h2 B-1-549 4-a2 CO h3 B-1-550 4-a2CH₂ h3 B-1-551 4-a2 CO h4 B-1-552 4-a2 CH₂ h4 B-1-553 4-a2 CO h5 B-1-5544-a2 CH₂ h5 B-1-555 4-a2 CO h6 B-1-556 4-a2 CH₂ h6 B-1-557 4-a2 CO h7B-1-558 4-a2 CH₂ h7 B-1-559 4-a2 CO h8 B-1-560 4-a2 CH₂ h8 B-1-561 3-a2CO h1 B-1-562 3-a2 CH₂ h1 B-1-563 3-a2 CO h2 B-1-564 3-a2 CH₂ h2 B-1-5653-a2 CO h3 B-1-566 3-a2 CH₂ h3 B-1-567 3-a2 CO h4 B-1-568 3-a2 CH₂ h4B-1-569 3-a2 CO h5 B-1-570 3-a2 CH₂ h5 B-1-571 3-a2 CO h6 B-1-572 3-a2CH₂ h6 B-1-573 3-a2 CO h7 B-1-574 3-a2 CH₂ h7 B-1-575 3-a2 CO h8 B-1-5763-a2 CH₂ h8

TABLE 10

Compound Physical Constant No. A D Z [ ] m.p. ° C. B-1-577 4-a1 CO h1B-1-578 4-a1 CH₂ h1 n_(D) ^(20.5)1.5668 B-1-579 4-a1 CO h2 B-1-580 4-a1CH₂ h2 B-1-581 4-a1 CO h3 B-1-582 4-a1 CH₂ h3 B-1-583 4-a1 CO h4 B-1-5844-a1 CH₂ h4 B-1-585 4-a1 CO h5 B-1-586 4-a1 CH₂ h5 B-1-587 4-a1 CO h6B-1-588 4-a1 CH₂ h6 B-1-589 4-a1 CO h7 B-1-590 4-a1 CH₂ h7 B-1-591 4-a1CO h8 B-1-592 4-a1 CH₂ h8 B-1-593 3-a1 CO h1 B-1-594 3-a1 CH₂ h1 B-1-5953-a1 CO h2 B-1-596 3-a1 CH₂ h2 B-1-597 3-a1 CO h3 B-1-598 3-a1 CH₂ h3B-1-599 3-a1 CO h4 B-1-600 3-a1 CH₂ h4 B-1-601 3-a1 CO h5 B-1-602 3-a1CH₂ h5 B-1-603 3-a1 CO h6 B-1-604 3-a1 CH₂ h6 B-1-605 3-a1 CO h7 B-1-6063-a1 CH₂ h7 B-1-607 3-a1 CO h8 B-1-608 3-a1 CH₂ h8 B-1-609 4-a2 CO h1B-1-610 4-a2 CH₂ h1 B-1-611 4-a2 CO h2 B-1-612 4-a2 CH₂ h2 B-1-613 4-a2CO h3 B-1-614 4-a2 CH₂ h3 B-1-615 4-a2 CO h4 B-1-616 4-a2 CH₂ h4 B-1-6174-a2 CO h5 B-1-618 4-a2 CH₂ h5 B-1-619 4-a2 CO h6 B-1-620 4-a2 CH₂ h6B-1-621 4-a2 CO h7 B-1-622 4-a2 CH₂ h7 B-1-623 4-a2 CO h8 B-1-624 4-a2CH₂ h8 B-1-625 3-a2 CO h1 B-1-626 3-a2 CH₂ h1 B-1-627 3-a2 CO h2 B-1-6283-a2 CH₂ h2 B-1-629 3-a2 CO h3 B-1-630 3-a2 CH₂ h3 B-1-631 3-a2 CO h4B-1-632 3-a2 CH₂ h4 B-1-633 3-a2 CO h5 B-1-634 3-a2 CH₂ h5 B-1-635 3-a2CO h6 B-1-636 3-a2 CH₂ h6 B-1-637 3-a2 CO h7 B-1-638 3-a2 CH₂ h7 B-1-6393-a2 CO h8 B-1-640 3-a2 CH₂ h8

TABLE 11

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R₄R_(1a) R_(1b) D Z index B-2-1-1 H H H H CH₂ h1 n_(D) ^(20.4) 1.5693B-2-1-2 H H H H CH₂ h2 [50-52] B-2-1-3 H H H H CH₂ h3 [81-84] B-2-1-4 HH H H CH₂ h4 & NMR B-2-1-5 H H H H CH₂ h5 [158-160] B-2-1-6 H H H H CH₂h6 n_(D) ^(20.1) 1.5531 B-2-1-7 H H H H CH₂ h7 n_(D) ^(20.7) 1.5472B-2-1-8 H H H H CH₂ h8 [90-93] B-2-1-9 H H H H CH₂CH₂ h1 B-2-1-10 H H HH CH₂CH₂ h2 B-2-1-11 H H H H CH₂CH₂ h3 B-2-1-12 H H H H CH₂CH₂ h4B-2-1-13 H H H H CH₂CH₂ h5 B-2-1-14 H H H H CH₂CH₂ h6 B-2-1-15 H H H HCH₂CH₂ h7 B-2-1-16 H H H H CH₂CH₂ h8 B-2-1-17 H H H H CH₂CH₂CH₂ h1B-2-1-18 H H H H CH₂CH₂CH₂ h2 B-2-1-19 H H H H CH₂CH₂CH₂ h3 B-2-1-20 H HH H CH₂CH₂CH₂ h4 B-2-1-21 H H H H CH₂CH₂CH₂ h5 B-2-1-22 H H H HCH₂CH₂CH₂ h6 & NMR B-2-1-23 H H H H CH₂CH₂CH₂ h7 B-2-1-24 H H H HCH₂CH₂CH₂ h8 B-2-1-25 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-1-26 H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-1-27 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-1-28 HH H H CH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-1-29 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5B-2-1-30 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h6 n_(D) ^(21.4) 1.5379 B-2-1-31 H HH H CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-1-32 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8B-2-1-33 CH₃ H H H CH₂ h1 B-2-1-34 CH₃ H H H CH₂ h2 B-2-1-35 CH₃ H H HCH₂ h3 B-2-1-36 CH₃ H H H CH₂ h4 B-2-1-37 CH₃ H H H CH₂ h5 B-2-1-38 CH₃H H H CH₂ h6 B-2-1-39 CH₃ H H H CH₂ h7 B-2-1-40 CH₃ H H H CH₂ h8B-2-1-41 CH₂CH₃ H H H CH₂ h1 B-2-1-42 CH₂CH₃ H H H CH₂ h2 B-2-1-43CH₂CH₃ H H H CH₂ h3 B-2-1-44 CH₂CH₃ H H H CH₂ h4 B-2-1-45 CH₂CH₃ H H HCH₂ h5 B-2-1-46 CH₂CH₃ H H H CH₂ h6 B-2-1-47 CH₂CH₃ H H H CH₂ h7B-2-1-48 CH₂CH₃ H H H CH₂ h8 B-2-1-49 CH₂CH₂CH₃ H H H CH₂ h1 B-2-1-50CH₂CH₂CH₃ H H H CH₂ h2 B-2-1-51 CH₂CH₂CH₃ H H H CH₂ h3 B-2-1-52CH₂CH₂CH₃ H H H CH₂ h4 B-2-1-53 CH₂CH₂CH₃ H H H CH₂ h5 B-2-1-54CH₂CH₂CH₃ H H H CH₂ h6 B-2-1-55 CH₂CH₂CH₃ H H H CH₂ h7 B-2-1-56CH₂CH₂CH₃ H H H CH₂ h8 B-2-1-57 CH(CH₃)₂ H H H CH₂ h1 B-2-1-58 CH(CH₃)₂H H H CH₂ h2 B-2-1-59 CH(CH₃)₂ H H H CH₂ h3 B-2-1-60 CH(CH₃)₂ H H H CH₂h4 B-2-1-61 CH(CH₃)₂ H H H CH₂ h5 B-2-1-62 CH(CH₃)₂ H H H CH₂ h6B-2-1-63 CH(CH₃)₂ H H H CH₂ h7 B-2-1-64 CH(CH₃)₂ H H H CH₂ h8 B-2-1-65CH₂C₆H₅ H H H CH₂ h1 B-2-1-66 CH₂C₆H₅ H H H CH₂ h2 B-2-1-67 CH₂C₆H₅ H HH CH₂ h3 B-2-1-68 CH₂C₆H₅ H H H CH₂ h4 B-2-1-69 CH₂C₆H₅ H H H CH₂ h5B-2-1-70 CH₂C₆H₅ H H H CH₂ h6 B-2-1-71 CH₂C₆H₅ H H H CH₂ h7 B-2-1-72CH₂C₆H₅ H H H CH₂ h8 B-2-1-73 H CH₃ H H CH₂ h1 [78-81] B-2-1-74 H CH₃ HH CH₂ h2 B-2-1-75 H CH₃ H H CH₂ h3 B-2-1-76 H CH₃ H H CH₂ h4 B-2-1-77 HCH₃ H H CH₂ h5 B-2-1-78 H CH₃ H H CH₂ h6 B-2-1-79 H CH₃ H H CH₂ h7B-2-1-80 H CH₃ H H CH₂ h8 B-2-1-81 H H CH₃ H CH₂ h1 B-2-1-82 H H CH₃ HCH₂ h2 B-2-1-83 H H CH₂ H CH₂ h3 B-2-1-84 H H CH₃ H CH₂ h4 B-2-1-85 H HCH₃ H CH₂ h5 B-2-1-86 H H CH₃ H CH₂ h6 B-2-1-87 H H CH₃ H CH₂ h7B-2-1-88 H H CH₃ H CH₂ h8 B-2-1-89 H H Cl H CH₂ h1 B-2-1-90 H H Cl H CH₂h2 B-2-1-91 H H Cl H CH₂ h3 B-2-1-92 H H Cl H CH₂ h4 B-2-1-93 H H Cl HCH₂ h5 B-2-1-94 H H Cl H CH₂ h6 B-2-1-95 H H Cl H CH₂ h7 B-2-1-96 H H ClH CH₂ h8 B-2-1-97 H H F H CH₂ h1 B-2-1-98 H H F H CH₂ h2 B-2-1-99 H H FH CH₂ h3 B-2-1-100 H H F H CH₂ h4 B-2-1-101 H H F H CH₂ h5 B-2-1-102 H HF H CH₂ h6 B-2-1-103 H H F H CH₂ h7 B-2-1-104 H H F H CH₂ h8 B-2-1-105 HH H CH₃ CH₂ h1 [156-158] B-2-1-106 H H H CH₃ CH₂ h2 B-2-1-107 H H H CH₃CH₂ h3 B-2-1-108 H H H CH₃ CH₂ h4 B-2-1-109 H H H CH₃ CH₂ h5 B-2-1-110 HH H CH₃ CH₂ h6 B-2-1-111 H H H CH₃ CH₂ h7 B-2-1-112 H H H CH₃ CH₂ h8B-2-1-113 H H H Cl CH₂ h1 B-2-1-114 H H H Cl CH₂ h2 B-2-1-115 H H H ClCH₂ h3 B-2-1-116 H H H Cl CH₂ h4 B-2-1-117 H H H Cl CH₂ h5 B-2-1-118 H HH Cl CH₂ h6 B-2-1-119 H H H Cl CH₂ h7 B-2-1-120 H H H Cl CH₂ h8B-2-1-121 H H H F CH₂ h1 B-2-1-122 H H H F CH₂ h2 B-2-1-123 H H H F CH₂h3 B-2-1-124 H H H F CH₂ h4 B-2-1-125 H H H F CH₂ h5 B-2-1-126 H H H FCH₂ h6 B-2-1-127 H H H F CH₂ h7 B-2-1-128 H H H F CH₂ h8

TABLE 12

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R₄ D Zindex B-2-2-1 H H CH₂ H1 [211-216] B-2-2-2 H H CH₂ h2 & NMR B-2-2-3 H HCH₂ h3 [175-178] B-2-2-4 H H CH₂ h4 B-2-2-5 H H CH₂ h5 [63-66] B-2-2-6 HH CH₂ h6 n_(D) ^(20.5) 1.5529 B-2-2-7 H H CH₂ h7 B-2-2-8 H H CH₂ h8B-2-2-9 H H CH₂CH₂ h1 B-2-2-10 H H CH₂CH₂ h2 B-2-2-11 H H CH₂CH₂ h3B-2-2-12 H H CH₂CH₂ h4 B-2-2-13 H H CH₂CH₂ h5 B-2-2-14 H H CH₂CH₂ h6B-2-2-15 H H CH₂CH₂ h7 B-2-2-16 H H CH₂CH₂ h8 B-2-2-17 H H CH₂CH₂CH₂ h1B-2-2-18 H H CH₂CH₂CH₂ h2 B-2-2-19 H H CH₂CH₂CH₂ h3 B-2-2-20 H HCH₂CH₂CH₂ h4 B-2-2-21 H H CH₂CH₂CH₂ h5 B-2-2-22 H H CH₂CH₂CH₂ h6B-2-2-23 H H CH₂CH₂CH₂ h7 B-2-2-24 H H CH₂CH₂CH₂ h8 B-2-2-25 H HCH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-2-26 H H CH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-2-27 H HCH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-2-28 H H CH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-2-29 H HCH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-2-30 H H CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-2-31 H HCH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-2-32 H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-2-33 CH₃ HCH₂ h1 B-2-2-34 CH₃ H CH₂ h2 B-2-2-35 CH₃ H CH₂ h3 B-2-2-36 CH₃ H CH₂ h4B-2-2-37 CH₃ H CH₂ h5 B-2-2-38 CH₃ H CH₂ h6 B-2-2-39 CH₃ H CH₂ h7B-2-2-40 CH₃ H CH₂ h8 B-2-2-41 CH₂CH₃ H CH₂ h1 B-2-2-42 CH₂CH₃ H CH₂ h2B-2-2-43 CH₂CH₃ H CH₂ h3 B-2-2-44 CH₂CH₃ H CH₂ h4 B-2-2-45 CH₂CH₃ H CH₂h5 B-2-2-46 CH₂CH₃ H CH₂ h6 B-2-2-47 CH₂CH₃ H CH₂ h7 B-2-2-48 CH₂CH₃ HCH₂ h8 B-2-2-49 CH₂CH₂CH₃ H CH₂ h1 B-2-2-50 CH₂CH₂CH₃ H CH₂ h2 B-2-2-51CH₂CH₂CH₃ H CH₂ h3 B-2-2-52 CH₂CH₂CH₃ H CH₂ h4 B-2-2-53 CH₂CH₂CH₃ H CH₂h5 B-2-2-54 CH₂CH₂CH₃ H CH₂ h6 B-2-2-55 CH₂CH₂CH₃ H CH₂ h7 B-2-2-56CH₂CH₂CH₃ H CH₂ h8 B-2-2-57 CH(CH₃)₂ H CH₂ h1 B-2-2-58 CH(CH₃)₂ H CH₂ h2B-2-2-59 CH(CH₃)₂ H CH₂ h3 B-2-2-60 CH(CH₃)₂ H CH₂ h4 B-2-2-61 CH(CH₃)₂H CH₂ h5 B-2-2-62 CH(CH₃)₂ H CH₂ h6 B-2-2-63 CH(CH₃)₂ H CH₂ h7 B-2-2-64CH(CH₃)₂ H CH₂ h8 B-2-2-65 CH₂C₆H₅ H CH₂ h1 B-2-2-66 CH₂C₆H₅ H CH₂ h2B-2-2-67 CH₂C₆H₅ H CH₂ h3 B-2-2-68 CH₂C₆H₅ H CH₂ h4 B-2-2-69 CH₂C₆H₅ HCH₂ h5 B-2-2-70 CH₂C₆H₅ H CH₂ h6 B-2-2-71 CH₂C₆H₅ H CH₂ h7 B-2-2-72CH₂C₆H₅ H CH₂ h8 B-2-2-73 H CH₃ CH₂ h1 B-2-2-74 H CH₃ CH₂ h2 B-2-2-75 HCH₃ CH₂ h3 B-2-2-76 H CH₃ CH₂ h4 B-2-2-77 H CH₃ CH₂ h5 B-2-2-78 H CH₃CH₂ h6 B-2-2-79 H CH₃ CH₂ h7 B-2-2-80 H CH₃ CH₂ h8

TABLE 13

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R₆R_(1a) R_(1b) D Z index B-2-3-1 H H H H CH₂ h1 B-2-3-2 H H H H CH₂ h2B-2-3-3 H H H H CH₂ h3 B-2-3-4 H H H H CH₂ h4 B-2-3-5 H H H H CH₂ h5B-2-3-6 H H H H CH₂ h6 B-2-3-7 H H H H CH₂ h7 B-2-3-8 H H H H CH₂ h8B-2-3-9 H H H H CH₂CH₂ h1 B-2-3-10 H H H H CH₂CH₂ h2 B-2-3-11 H H H HCH₂CH₂ h3 B-2-3-12 H H H H CH₂CH₂ h4 B-2-3-13 H H H H CH₂CH₂ h5 B-2-3-14H H H H CH₂CH₂ h6 B-2-3-15 H H H H CH₂CH₂ h7 B-2-3-16 H H H H CH₂CH₂ h8B-2-3-17 H H H H CH₂CH₂CH₂ h1 B-2-3-18 H H H H CH₂CH₂CH₂ h2 B-2-3-19 H HH H CH₂CH₂CH₂ h3 B-2-3-20 H H H H CH₂CH₂CH₂ h4 B-2-3-21 H H H HCH₂CH₂CH₂ h5 B-2-3-22 H H H H CH₂CH₂CH₂ h6 B-2-3-23 H H H H CH₂CH₂CH₂ h7B-2-3-24 H H H H CH₂CH₂CH₂ h8 B-2-3-25 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h1B-2-3-26 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-3-27 H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-3-28 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-3-29 HH H H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-3-30 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h6B-2-3-31 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-3-32 H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-3-33 CH₃ H H H CH₂ h1 B-2-3-34 CH₃ H H H CH₂h2 B-2-3-35 CH₃ H H H CH₂ h3 B-2-3-36 CH₃ H H H CH₂ h4 B-2-3-37 CH₃ H HH CH₂ h5 B-2-3-38 CH₃ H H H CH₂ h6 B-2-3-39 CH₃ H H H CH₂ h7 B-2-3-40CH₃ H H H CH₂ h8 B-2-3-41 CH₂CH₃ H H H CH₂ h1 B-2-3-42 CH₂CH₃ H H H CH₂h2 B-2-3-43 CH₂CH₃ H H H CH₂ h3 B-2-3-44 CH₂CH₃ H H H CH₂ h4 B-2-3-45CH₂CH₃ H H H CH₂ h5 B-2-3-46 CH₂CH₃ H H H CH₂ h6 B-2-3-47 CH₂CH₃ H H HCH₂ h7 B-2-3-48 CH₂CH₃ H H H CH₂ h8 B-2-3-49 CH₂CH₂CH₃ H H H CH₂ h1B-2-3-50 CH₂CH₂CH₃ H H H CH₂ h2 B-2-3-51 CH₂CH₂CH₃ H H H CH₂ h3 B-2-3-52CH₂CH₂CH₃ H H H CH₂ h4 B-2-3-53 CH₂CH₂CH₃ H H H CH₂ h5 B-2-3-54CH₂CH₂CH₃ H H H CH₂ h6 B-2-3-55 CH₂CH₂CH₃ H H H CH₂ h7 B-2-3-56CH₂CH₂CH₃ H H H CH₂ h8 B-2-3-57 CH(CH₃)₂ H H H CH₂ h1 B-2-3-58 CH(CH₃)₂H H H CH₂ h2 B-2-3-59 CH(CH₃)₂ H H H CH₂ h3 B-2-3-60 CH(CH₃)₂ H H H CH₂h4 B-2-3-61 CH(CH₃)₂ H H H CH₂ h5 B-2-3-62 CH(CH₃)₂ H H H CH₂ h6B-2-3-63 CH(CH₃)₂ H H H CH₂ h7 B-2-3-64 CH(CH₃)₂ H H H CH₂ h8 B-2-3-65CH₂C₆H₅ H H H CH₂ h1 B-2-3-66 CH₂C₆H₅ H H H CH₂ h2 B-2-3-67 CH₂C₆H₅ H HH CH₂ h3 B-2-3-68 CH₂C₆H₅ H H H CH₂ h4 B-2-3-69 CH₂C₆H₅ H H H CH₂ h5B-2-3-70 CH₂C₆H₅ H H H CH₂ h6 B-2-3-71 CH₂C₆H₅ H H H CH₂ h7 B-2-3-72CH₂C₆H₅ H H H CH₂ h8 B-2-3-73 H CH₃ H H CH₂ h1 B-2-3-74 H CH₃ H H CH₂ h2B-2-3-75 H CH₃ H H CH₂ h3 B-2-3-76 H CH₃ H H CH₂ h4 B-2-3-77 H CH₃ H HCH₂ h5 B-2-3-78 H CH₃ H H CH₂ h6 B-2-3-79 H CH₃ H H CH₂ h7 B-2-3-80 HCH₃ H H CH₂ h8 B-2-3-81 H H CH₃ H CH₂ h1 B-2-3-82 H H CH₃ H CH₂ h2B-2-3-83 H H CH₃ H CH₂ h3 B-2-3-84 H H CH₃ H CH₂ h4 B-2-3-85 H H CH₃ HCH₂ h5 B-2-3-86 H H CH₃ H CH₂ h6 B-2-3-87 H H CH₃ H CH₂ h7 B-2-3-88 H HCH₃ H CH₂ h8 B-2-3-89 H H Cl H CH₂ h1 B-2-3-90 H H Cl H CH₂ h2 B-2-3-91H H Cl H CH₂ h3 B-2-3-92 H H Cl H CH₂ h4 B-2-3-93 H H Cl H CH₂ h5B-2-3-94 H H Cl H CH₂ h6 B-2-3-95 H H Cl H CH₂ h7 B-2-3-96 H H Cl H CH₂h8 B-2-3-97 H H F H CH₂ h1 B-2-3-98 H H F H CH₂ h2 B-2-3-99 H H F H CH₂h3 B-2-3-100 H H F H CH₂ h4 B-2-3-101 H H F H CH₂ h5 B-2-3-102 H H F HCH₂ h6 B-2-3-103 H H F H CH₂ h7 B-2-3-104 H H F H CH₂ h8 B-2-3-105 H H HCH₃ CH₂ h1 B-2-3-106 H H H CH₃ CH₂ h2 B-2-3-107 H H H CH₃ CH₂ h3B-2-3-108 H H H CH₃ CH₂ h4 B-2-3-109 H H H CH₃ CH₂ h5 B-2-3-110 H H HCH₃ CH₂ h6 B-2-3-111 H H H CH₃ CH₂ h7 B-2-3-112 H H H CH₃ CH₂ h8B-2-3-113 H H H Cl CH₂ h1 B-2-3-114 H H H Cl CH₂ h2 B-2-3-115 H H H ClCH₂ h3 B-2-3-116 H H H Cl CH₂ h4 B-2-3-117 H H H Cl CH₂ h5 B-2-3-118 H HH Cl CH₂ h6 B-2-3-119 H H H Cl CH₂ h7 B-2-3-120 H H H Cl CH₂ h8B-2-3-121 H H H F CH₂ h1 B-2-3-122 H H H F CH₂ h2 B-2-3-123 H H H F CH₂h3 B-2-3-124 H H H F CH₂ h4 B-2-3-125 H H H F CH₂ h5 B-2-3-126 H H H FCH₂ h6 B-2-3-127 H H H F CH₂ h7 B-2-3-128 H H H F CH₂ h8

TABLE 14

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R_(6a)R_(6b) R_(1a) R_(1b) D Z index B-2-4-1 H H H H H CH₂ h1  [98-102]B-2-4-2 H H H H H CH₂ h2 B-2-4-3 H H H H H CH₂ h3 B-2-4-4 H H H H H CH₂h4 B-2-4-5 H H H H H CH₂ h5 B-2-4-6 H H H H H CH₂ h6 B-2-4-7 H H H H HCH₂ h7 B-2-4-8 H H H H H CH₂ h8 B-2-4-9 H H H H H CH₂CH₂ h1 B-2-4-10 H HH H H CH₂CH₂ h2 B-2-4-11 H H H H H CH₂CH₂ h3 B-2-4-12 H H H H H CH₂CH₂h4 B-2-4-13 H H H H H CH₂CH₂ h5 B-2-4-14 H H H H H CH₂CH₂ h6 B-2-4-15 HH H H H CH₂CH₂ h7 B-2-4-16 H H H H H CH₂CH₂ h8 B-2-4-17 H H H H HCH₂CH₂CH₂ h1 B-2-4-18 H H H H H CH₂CH₂CH₂ h2 B-2-4-19 H H H H HCH₂CH₂CH₂ h3 B-2-4-20 H H H H H CH₂CH₂CH₂ h4 B-2-4-21 H H H H HCH₂CH₂CH₂ h5 B-2-4-22 H H H H H CH₂CH₂CH₂ h6 B-2-4-23 H H H H HCH₂CH₂CH₂ h7 B-2-4-24 H H H H H CH₂CH₂CH₂ h8 B-2-4-25 H H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-4-26 H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-4-27H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-4-28 H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h4B-2-4-29 H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-4-30 H H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-4-31 H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-4-32H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-4-33 CH₃ H H H H CH₂ h1 B-2-4-34 CH₃H H H H CH₂ h2 B-2-4-35 CH₃ H H H H CH₂ h3 B-2-4-36 CH₃ H H H H CH₂ h4B-2-4-37 CH₃ H H H H CH₂ h5 B-2-4-38 CH₃ H H H H CH₂ h6 B-2-4-39 CH₃ H HH H CH₂ h7 B-2-4-40 CH₃ H H H H CH₂ h8 B-2-4-41 CH₂CH₃ H H H H CH₂ h1B-2-4-42 CH₂CH₃ H H H H CH₂ h2 B-2-4-43 CH₂CH₃ H H H H CH₂ h3 B-2-4-44CH₂CH₃ H H H H CH₂ h4 B-2-4-45 CH₂CH₃ H H H H CH₂ h5 B-2-4-46 CH₂CH₃ H HH H CH₂ h6 B-2-4-47 CH₂CH₃ H H H H CH₂ h7 B-2-4-48 CH₂CH₃ H H H H CH₂ h8B-2-4-49 CH₂CH₂CH₃ H H H H CH₂ h1 B-2-4-50 CH₂CH₂CH₃ H H H H CH₂ h2B-2-4-51 CH₂CH₂CH₃ H H H H CH₂ h3 B-2-4-52 CH₂CH₂CH₃ H H H H CH₂ h4B-2-4-53 CH₂CH₂CH₃ H H H H CH₂ h5 B-2-4-54 CH₂CH₂CH₃ H H H H CH₂ h6B-2-4-55 CH₂CH₂CH₃ H H H H CH₂ h7 B-2-4-56 CH₂CH₂CH₃ H H H H CH₂ h8B-2-4-57 CH(CH₃)₂ H H H H CH₂ h1 B-2-4-58 CH(CH₃)₂ H H H H CH₂ h2B-2-4-59 CH(CH₃)₂ H H H H CH₂ h3 B-2-4-60 CH(CH₃)₂ H H H H CH₂ h4B-2-4-61 CH(CH₃)₂ H H H H CH₂ h5 B-2-4-62 CH(CH₃)₂ H H H H CH₂ h6B-2-4-63 CH(CH₃)₂ H H H H CH₂ h7 B-2-4-64 CH(CH₃)₂ H H H H CH₂ h8B-2-4-65 CH₂C₆H₅ H H H H CH₂ h1 B-2-4-66 CH₂C₆H₅ H H H H CH₂ h2 B-2-4-67CH₂C₆H₅ H H H H CH₂ h3 B-2-4-68 CH₂C₆H₅ H H H H CH₂ h4 B-2-4-69 CH₂C₆H₅H H H H CH₂ h5 B-2-4-70 CH₂C₆H₅ H H H H CH₂ h6 B-2-4-71 CH₂C₆H₅ H H H HCH₂ h7 B-2-4-72 CH₂C₆H₅ H H H H CH₂ h8 B-2-4-73 H CH₃ H H H CH₂ h1[80-85] B-2-4-74 H CH₃ H H H CH₂ h2 B-2-4-75 H CH₃ H H H CH₂ h3 B-2-4-76H CH₃ H H H CH₂ h4 B-2-4-77 H CH₃ H H H CH₂ h5 B-2-4-78 H CH₃ H H H CH₂h6 B-2-4-79 H CH₃ H H H CH₂ h7 B-2-4-80 H CH₃ H H H CH₂ h8 B-2-4-81 H HCH₃ H H CH₂ h1 [>300] B-2-4-82 H H CH₃ H H CH₂ h2 B-2-4-83 H H CH₃ H HCH₂ h3 B-2-4-84 H H CH₃ H H CH₂ h4 B-2-4-85 H H CH₃ H H CH₂ h5 B-2-4-86H H CH₃ H H CH₂ h6 B-2-4-87 H H CH₃ H H CH₂ h7 B-2-4-88 H H CH₃ H H CH₂h8 B-2-4-89 H H H CH₃ H CH₂ h1 B-2-4-90 H H H CH₃ H CH₂ h2 B-2-4-91 H HH CH₃ H CH₂ h3 B-2-4-92 H H H CH₃ H CH₂ h4 B-2-4-93 H H H CH₃ H CH₂ h5B-2-4-94 H H H CH₃ H CH₂ h6 B-2-4-95 H H H CH₃ H CH₂ h7 B-2-4-96 H H HCH₃ H CH₂ h8 B-2-4-97 H H H Cl H CH₂ h1 B-2-4-98 H H H Cl H CH₂ h2B-2-4-99 H H H Cl H CH₂ h3 B-2-4-100 H H H Cl H CH₂ h4 B-2-4-101 H H HCl H CH₂ h5 B-2-4-102 H H H Cl H CH₂ h6 B-2-4-103 H H H Cl H CH₂ h7B-2-4-104 H H H Cl H CH₂ h8 B-2-4-105 H H H F H CH₂ h1 B-2-4-106 H H H FH CH₂ h2 B-2-4-107 H H H F H CH₂ h3 B-2-4-108 H H H F H CH₂ h4 B-2-4-109H H H F H CH₂ h5 B-2-4-110 H H H F H CH₂ h6 B-2-4-111 H H H F H CH₂ h7B-2-4-112 H H H F H CH₂ h8 B-2-4-113 H H H H CH₃ CH₂ h1 B-2-4-114 H H HH CH₃ CH₂ h2 B-2-4-115 H H H H CH₃ CH₂ h3 B-2-4-116 H H H H CH₃ CH₂ h4B-2-4-117 H H H H CH₃ CH₂ h5 B-2-4-118 H H H H CH₃ CH₂ h6 B-2-4-119 H HH H CH₃ CH₂ h7 B-2-4-120 H H H H CH₃ CH₂ h8 B-2-4-121 H H H H Cl CH₂ h1B-2-4-122 H H H H Cl CH₂ h2 B-2-4-123 H H H H Cl CH₂ h3 B-2-4-124 H H HH Cl CH₂ h4 B-2-4-125 H H H H Cl CH₂ h5 B-2-4-126 H H H H Cl CH₂ h6B-2-4-127 H H H H Cl CH₂ h7 B-2-4-128 H H H H Cl CH₂ h8 B-2-4-129 H H HH F CH₂ h1 B-2-4-130 H H H H F CH₂ h2 B-2-4-131 H H H H F CH₂ h3B-2-4-132 H H H H F CH₂ h4 B-2-4-133 H H H H F CH₂ h5 B-2-4-134 H H H HF CH₂ h6 B-2-4-135 H H H H F CH₂ h7 B-2-4-136 H H H H F CH₂ h8

TABLE 15

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R₅R_(6a) R_(6b) R_(1a) R_(1b) D Z index B-2-5-1 H H H H H H CH₂ h1[103-108] B-2-5-2 H H H H H H CH₂ h1 [176-180] B-2-5-3 H H H H H H CH₂h2 2HCl salt B-2-5-4 H H H H H H CH₂ h3 [80-82] B-2-5-5 H H H H H H CH₂h4 [132-135] B-2-5-6 H H H H H H CH₂ h5 B-2-5-7 H H H H H H CH₂ h6[110-115] B-2-5-8 H H H H H H CH₂ h7 & NMR B-2-5-9 H H H H H H CH₂ h8B-2-5-10 H H H H H H CH₂CH₂ h1 B-2-5-11 H H H H H H CH₂CH₂ h2 B-2-5-12 HH H H H H CH₂CH₂ h3 B-2-5-13 H H H H H H CH₂CH₂ h4 B-2-5-14 H H H H H HCH₂CH₂ h5 B-2-5-15 H H H H H H CH₂CH₂ h6 B-2-5-16 H H H H H H CH₂CH₂ h7B-2-5-17 H H H H H H CH₂CH₂ h8 B-2-5-18 H H H H H H CH₂CH₂CH₂ h1B-2-5-19 H H H H H H CH₂CH₂CH₂ h2 n_(D) ^(20.4) 1.5758 B-2-5-20 H H H HH H CH₂CH₂CH₂ h3 B-2-5-21 H H H H H H CH₂CH₂CH₂ h4 B-2-5-22 H H H H H HCH₂CH₂CH₂ h5 B-2-5-23 H H H H H H CH₂CH₂CH₂ h6 B-2-5-24 H H H H H HCH₂CH₂CH₂ h7 B-2-5-25 H H H H H H CH₂CH₂CH₂ h8 B-2-5-26 H H H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-5-27 H H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h2B-2-5-28 H H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-5-29 H H H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-5-30 H H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5B-2-5-31 H H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-5-32 H H H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-5-33 H H H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8B-2-5-34 CH₃ H H H H H CH₂ h1 [113-117] B-2-5-35 CH₃ H H H H H CH₂ h2B-2-5-36 CH₃ H H H H H CH₂ h3 B-2-5-37 CH₃ H H H H H CH₂ h4 B-2-5-38 CH₃H H H H H CH₂ h5 B-2-5-39 CH₃ H H H H H CH₂ h6 B-2-5-40 CH₃ H H H H HCH₂ h7 B-2-5-41 CH₃ H H H H H CH₂ h8 B-2-5-42 CH₂CH₃ H H H H H CH₂ h1[95-99] B-2-5-43 CH₂CH₃ H H H H H CH₂ h2 B-2-5-44 CH₂CH₃ H H H H H CH₂h3 B-2-5-45 CH₂CH₃ H H H H H CH₂ h4 B-2-5-46 CH₂CH₃ H H H H H CH₂ h5B-2-5-47 CH₂CH₃ H H H H H CH₂ h6 B-2-5-48 CH₂CH₃ H H H H H CH₂ h7B-2-5-49 CH₂CH₃ H H H H H CH₂ h8 B-2-5-50 CH₂CH₂CH₃ H H H H H CH₂ h1B-2-5-51 CH₂CH₂CH₃ H H H H H CH₂ h2 B-2-5-52 CH₂CH₂CH₃ H H H H H CH₂ h3B-2-5-53 CH₂CH₂CH₃ H H H H H CH₂ h4 B-2-5-54 CH₂CH₂CH₃ H H H H H CH₂ h5B-2-5-55 CH₂CH₂CH₃ H H H H H CH₂ h6 B-2-5-56 CH₂CH₂CH₃ H H H H H CH₂ h7B-2-5-57 CH₂CH₂CH₃ H H H H H CH₂ h8 B-2-5-58 CH(CH₃)₂ H H H H H CH₂ h1[89-92] B-2-5-59 CH(CH₃)₂ H H H H H CH₂ h2 B-2-5-60 CH(CH₃)₂ H H H H HCH₂ h3 B-2-5-61 CH(CH₃)₂ H H H H H CH₂ h4 B-2-5-62 CH(CH₃)₂ H H H H HCH₂ hS B-2-5-63 CH(CH₃)₂ H H H H H CH₂ h6 B-2-5-64 CH(CH₃)₂ H H H H HCH₂ h7 B-2-5-65 CH(CH₃)₂ H H H H H CH₂ h8 B-2-5-66 CH₂C₆H₅ H H H H H CH₂h1 B-2-5-67 CH₂C₆H₅ H H H H H CH₂ h2 B-2-5-68 CH₂C₆H₅ H H H H H CH₂ h3B-2-5-69 CH₂C₆H₅ H H H H H CH₂ h4 B-2-5-70 CH₂C₆H₅ H H H H H CH₂ h5B-2-5-71 CH₂C₆H₅ H H H H H CH₂ h6 B-2-5-72 CH₂C₆H₅ H H H H H CH₂ h7B-2-5-73 CH₂C₆H₅ H H H H H CH₂ h8 B-2-5-74 H CH₃ H H H H CH₂ h1[115-119] B-2-5-75 H CH₃ H H H H CH₂ h2 B-2-5-76 H CH₃ H H H H CH₂ h3B-2-5-77 H CH₃ H H H H CH₂ h4 B-2-5-78 H CH₃ H H H H CH₂ h5 B-2-5-79 HCH₃ H H H H CH₂ h6 B-2-5-80 H CH₃ H H H H CH₂ h7 B-2-5-81 H CH₃ H H H HCH₂ h8 B-2-5-82 H H CH₃ H H H CH₂ h1 [73-76] B-2-5-83 H H CH₃ H H H CH₂h2 B-2-5-84 H H CH₃ H H H CH₂ h3 B-2-5-85 H H CH₃ H H H CH₂ h4 B-2-5-86H H CH₃ H H H CH₂ h5 B-2-5-87 H H CH₃ H H H CH₂ h6 B-2-5-88 H H CH₃ H HH CH₂ h7 B-2-5-89 H H CH₃ H H H CH₂ h8 B-2-5-90 H H H CH₃ H H CH₂ h1[49-54] B-2-5-91 H H H CH₃ H H CH₂ h2 B-2-5-92 H H H CH₃ H H CH₂ h3B-2-5-93 H H H CH₃ H H CH₂ h4 B-2-5-94 H H H CH₃ H H CH₂ h5 B-2-5-95 H HH CH₃ H H CH₂ h6 B-2-5-96 H H H CH₃ H H CH₂ h7 B-2-5-97 H H H CH₃ H HCH₂ h8 B-2-5-98 H H

— H H CH₂ h1 [126-130] B-2-5-99 H H H H CH₃ H CH₂ h1 B-2-5-100 H H H HCH₃ H CH₂ h2 B-2-5-101 H H H H CH₃ H CH₂ h3 B-2-5-102 H H H H CH₃ H CH₂h4 B-2-5-103 H H H H CH₃ H CH₂ h5 B-2-5-104 H H H H CH₃ H CH₂ h6B-2-5-105 H H H H CH₃ H CH₂ h7 B-2-5-106 H H H H CH₃ H CH₂ h8 B-2-5-107H H H H Cl H CH₂ h1 B-2-5-108 H H H H Cl H CH₂ h2 B-2-5-109 H H H H Cl HCH₂ h3 B-2-5-110 H H H H Cl H CH₂ h4 B-2-5-111 H H H H Cl H CH₂ h5B-2-5-112 H H H H Cl H CH₂ h6 B-2-5-113 H H H H Cl H CH₂ h7 B-2-5-114 HH H H Cl F H CH₂ h8 B-2-5-115 H H H H F H CH₂ h1 B-2-5-116 H H H H F HCH₂ h2 B-2-5-117 H H H H F H CH₂ h3 B-2-5-118 H H H H F H CH₂ h4B-2-5-119 H H H H F H CH₂ h5 B-2-5-120 H H H H F H CH₂ h6 B-2-5-121 H HH H F H CH₂ h7 B-2-5-122 H H H H H H CH₂ h8 B-2-5-123 H H H H H CH₃ CH₂h1 B-2-5-124 H H H H H CH₃ CH₂ h2 B-2-5-125 H H H H H CH₃ CH₂ h3B-2-5-126 H H H H H CH₃ CH₂ h4 B-2-5-127 H H H H H CH₃ CH₂ h5 B-2-5-128H H H H H CH₃ CH₂ h6 B-2-5-129 H H H H H CH₃ CH₂ h7 B-2-5-130 H H H HCH₃ CH₂ h8 B-2-5-131 H H H H H Cl CH₂ h1 B-2-5-132 H H H H H Cl CH₂ h2B-2-5-133 H H H H H Cl CH₂ h3 B-2-5-134 H H H H H Cl CH₂ h4 B-2-5-135 HH H H H Cl CH₂ h5 B-2-5-136 H H H H H Cl CH₂ h6 B-2-5-137 H H H H H ClCH₂ h7 B-2-5-138 H H H H H Cl CH₂ h8 B-2-5-139 H H H H H F CH₂ h1B-2-5-140 H H H H H F CH₂ h2 B-2-5-141 H H H H H F CH₂ h3 B-2-5-142 H HH H H F CH₂ h4 B-2-5-143 H H H H H F CH₂ h5 B-2-5-144 H H H H H F CH₂ h6B-2-5-145 H H H H H F CH₂ h7 B-2-5-146 H H H H H F CH₂ h8

TABLE 16

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R₅R_(6a) R_(6b) D Z index B-2-6-1 H H H H CH₂ h1 [96-99] B-2-6-2 H H H HCH₂ h2 [75-80] B-2-6-3 H H H H CH₂ h3 B-2-6-4 H H H H CH₂ h4 B-2-6-5 H HH H CH₂ h5 [188-190] B-2-6-6 H H H H CH₂ h6 [89-92] B-2-6-7 H H H H CH₂h7 B-2-6-8 H H H H CH₂ h8 B-2-6-9 H H H H CH₂CH₂ h1 B-2-6-10 H H H HCH₂CH₂ h2 B-2-6-11 H H H H CH₂CH₂ h3 B-2-6-12 H H H H CH₂CH₂ h4 B-2-6-13H H H H CH₂CH₂ h5 B-2-6-14 H H H H CH₂CH₂ h6 B-2-6-15 H H H H CH₂CH₂ h7B-2-6-16 H H H H CH₂CH₂ h8 B-2-6-17 H H H H CH₂CH₂CH₂ h1 B-2-6-18 H H HH CH₂CH₂CH₂ h2 B-2-6-19 H H H H CH₂CH₂CH₂ h3 B-2-6-20 H H H H CH₂CH₂CH₂h4 B-2-6-21 H H H H CH₂CH₂CH₂ h5 B-2-6-22 H H H H CH₂CH₂CH₂ h6 B-2-6-23H H H H CH₂CH₂CH₂ h7 B-2-6-24 H H H H CH₂CH₂CH₂ h8 B-2-6-25 H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-6-26 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-6-27 HH H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-6-28 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h4B-2-6-29 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-6-30 H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-6-31 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-6-32 HH H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-6-33 CH₃ H H H CH₂ h1 B-2-6-34 CH₃ H H HCH₂ h2 B-2-6-35 CH₃ H H H CH₂ h3 B-2-6-36 CH₃ H H H CH₂ h4 B-2-6-37 CH₃H H H CH₂ h5 B-2-6-38 CH₃ H H H CH₂ h6 B-2-6-39 CH₃ H H H CH₂ h7B-2-6-40 CH₃ H H H CH₂ h8 B-2-6-41 CH₂CH₃ H H H CH₂ h1 B-2-6-42 CH₂CH₃ HH H CH₂ h2 B-2-6-43 CH₂CH₃ H H H CH₂ h3 B-2-6-44 CH₂CH₃ H H H CH₂ h4B-2-6-45 CH₂CH₃ H H H CH₂ h5 B-2-6-46 CH₂CH₃ H H H CH₂ h6 B-2-6-47CH₂CH₃ H H H CH₂ h7 B-2-6-48 CH₂CH₃ H H H CH₂ h8 B-2-6-49 CH₂CH₂CH₃ H HH CH₂ h1 B-2-6-50 CH₂CH₂CH₃ H H H CH₂ h2 B-2-6-51 CH₂CH₂CH₃ H H H CH₂ h3B-2-6-52 CH₂CH₂CH₃ H H H CH₂ h4 B-2-6-53 CH₂CH₂CH₃ H H H CH₂ h5 B-2-6-54CH₂CH₂CH₃ H H H CH₂ h6 B-2-6-55 CH₂CH₂CH₃ H H H CH₂ h7 B-2-6-56CH₂CH₂CH₃ H H H CH₂ h8 B-2-6-57 CH(CH₃)₂ H H H CH₂ h1 B-2-6-58 CH(CH₃)₂H H H CH₂ h2 B-2-6-59 CH(CH₃)₂ H H H CH₂ h3 B-2-6-60 CH(CH₃)₂ H H H CH₂h4 B-2-6-61 CH(CH₃)₂ H H H CH₂ h5 B-2-6-62 CH(CH₃)₂ H H H CH₂ h6B-2-6-63 CH(CH₃)₂ H H H CH₂ h7 B-2-6-64 CH(CH₃)₂ H H H CH₂ h8 B-2-6-65CH₂C₆H₅ H H H CH₂ h1 B-2-6-66 CH₂C₆H₅ H H H CH₂ h2 B-2-6-67 CH₂C₆H₅ H HH CH₂ h3 B-2-6-68 CH₂C₆H₅ H H H CH₂ h4 B-2-6-69 CH₂C₆H₅ H H H CH₂ h5B-2-6-70 CH₂C₆H₅ H H H CH₂ h6 B-2-6-71 CH₂C₆H₅ H H H CH₂ h7 B-2-6-72CH₂C₆H₅ H H H CH₂ h8 B-2-6-73 H CH₃ H H CH₂ h1 B-2-6-74 H CH₃ H H CH₂ h2B-2-6-75 H CH₃ H H CH₂ h3 B-2-6-76 H CH₃ H H CH₂ h4 B-2-6-77 H CH₃ H HCH₂ h5 B-2-6-78 H CH₃ H H CH₂ h6 B-2-6-79 H CH₃ H H CH₂ h7 B-2-6-80 HCH₃ H H CH₂ h8 B-2-6-81 H H CH₃ H CH₂ h1 B-2-6-82 H H CH₃ H CH₂ h2B-2-6-83 H H CH₃ H CH₂ h3 B-2-6-84 H H CH₃ H CH₂ h4 B-2-6-85 H H CH₃ HCH₂ h5 B-2-6-86 H H CH₃ H CH₂ h6 B-2-6-87 H H CH₃ H CH₂ h7 B-2-6-88 H HCH₃ H CH₂ h8 B-2-6-89 H H H CH₃ CH₂ h1 B-2-6-90 H H H CH₃ CH₂ h2B-2-6-91 H H H CH₃ CH₂ h3 B-2-6-92 H H H CH₃ CH₂ h4 B-2-6-93 H H H CH₃CH₂ h5 B-2-6-94 H H H CH₃ CH₂ h6 B-2-6-95 H H H CH₃ CH₂ h7 B-2-6-96 H HH CH₃ CH₂ h8

TABLE 17

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R_(1a)R_(1b) D Z index B-2-7-1 H H H CH₂ h1 [57-62] B-2-7-2 H H H CH₂ h2B-2-7-3 H H H CH₂ h3 B-2-7-4 H H H CH₂ h4 B-2-7-5 H H H CH₂ h5 B-2-7-6 HH H CH₂ h6 B-2-7-7 H H H CH₂ h7 B-2-7-8 H H H CH₂ h8 B-2-7-9 H H HCH₂CH₂ h1 B-2-7-10 H H H CH₂CH₂ h2 B-2-7-11 H H H CH₂CH₂ h3 B-2-7-12 H HH CH₂CH₂ h4 B-2-7-13 H H H CH₂CH₂ h5 B-2-7-14 H H H CH₂CH₂ h6 B-2-7-15 HH H CH₂CH₂ h7 B-2-7-16 H H H CH₂CH₂ h8 B-2-7-17 H H H CH₂CH₂CH₂ h1B-2-7-18 H H H CH₂CH₂CH₂ h2 B-2-7-19 H H H CH₂CH₂CH₂ h3 B-2-7-20 H H HCH₂CH₂CH₂ h4 B-2-7-21 H H H CH₂CH₂CH₂ h5 B-2-7-22 H H H CH₂CH₂CH₂ h6B-2-7-23 H H H CH₂CH₂CH₂ h7 B-2-7-24 H H H CH₂CH₂CH₂ h8 B-2-7-25 H H HCH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-7-26 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-7-27 H HH CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-7-28 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-7-29 HH H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-7-30 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-7-31H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-7-32 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8B-2-7-33 CH₃ H H CH₂ h1 B-2-7-34 CH₃ H H CH₂ h2 B-2-7-35 CH₃ H H CH₂ h3B-2-7-36 CH₃ H H CH₂ h4 B-2-7-37 CH₃ H H CH₂ h5 B-2-7-38 CH₃ H H CH₂ h6B-2-7-39 CH₃ H H CH₂ h7 B-2-7-40 CH₃ H H CH₂ h8 B-2-7-41 CH₂CH₃ H H CH₂h1 B-2-7-42 CH₂CH₃ H H CH₂ h2 B-2-7-43 CH₂CH₃ H H CH₂ h3 B-2-7-44 CH₂CH₃H H CH₂ h4 B-2-7-45 CH₂CH₃ H H CH₂ h5 B-2-7-46 CH₂CH₃ H H CH₂ h6B-2-7-47 CH₂CH₃ H H CH₂ h7 B-2-7-48 CH₂CH₃ H H CH₂ h8 B-2-7-49 CH₂CH₂CH₃H H CH₂ h1 B-2-7-50 CH₂CH₂CH₃ H H CH₂ h2 B-2-7-51 CH₂CH₂CH₃ H H CH₂ h3B-2-7-52 CH₂CH₂CH₃ H H CH₂ h4 B-2-7-53 CH₂CH₂CH₃ H H CH₂ h5 B-2-7-54CH₂CH₂CH₃ H H CH₂ h6 B-2-7-55 CH₂CH₂CH₃ H H CH₂ h7 B-2-7-56 CH₂CH₂CH₃ HH CH₂ h8 B-2-7-57 CH(CH₃)₂ H H CH₂ h1 B-2-7-58 CH(CH₃)₂ H H CH₂ h2B-2-7-59 CH(CH₃)₂ H H CH₂ h3 B-2-7-60 CH(CH₃)₂ H H CH₂ h4 B-2-7-61CH(CH₃)₂ H H CH₂ h5 B-2-7-62 CH(CH₃)₂ H H CH₂ h6 B-2-7-63 CH(CH₃)₂ H HCH₂ h7 B-2-7-64 CH(CH₃)₂ H H CH₂ h8 B-2-7-65 CH₂C₆H₅ H H CH₂ h1 B-2-7-66CH₂C₆H₅ H H CH₂ h2 B-2-7-67 CH₂C₆H₅ H H CH₂ h3 B-2-7-68 CH₂C₆H₅ H H CH₂h4 B-2-7-69 CH₂C₆H₅ H H CH₂ h5 B-2-7-70 CH₂C₆H₅ H H CH₂ h6 B-2-7-71CH₂C₆H₅ H H CH₂ h7 B-2-7-72 CH₂C₆H₅ H H CH₂ h8 B-2-7-73 H CH₃ H CH₂ h1B-2-7-74 H CH₃ H CH₂ h2 B-2-7-75 H CH₃ H CH₂ h3 B-2-7-76 H CH₃ H CH₂ h4B-2-7-77 H CH₃ H CH₂ h5 B-2-7-78 H CH₃ H CH₂ h6 B-2-7-79 H CH₃ H CH₂ h7B-2-7-80 H CH₃ H CH₂ h8 B-2-7-81 H Cl H CH₂ h1 B-2-7-82 H Cl H CH₂ h2B-2-7-83 H Cl H CH₂ h3 B-2-7-84 H Cl H CH₂ h4 B-2-7-85 H Cl H CH₂ h5B-2-7-86 H Cl H CH₂ h6 B-2-7-87 H Cl H CH₂ h7 B-2-7-88 H Cl H CH₂ h8B-2-7-89 H F H CH₂ h1 B-2-7-90 H F H CH₂ h2 B-2-7-91 H F H CH₂ h3B-2-7-92 H F H CH₂ h4 B-2-7-93 H F H CH₂ h5 B-2-7-94 H F H CH₂ h6B-2-7-95 H F H CH₂ h7 B-2-7-96 H F H CH₂ h8 B-2-7-97 H H CH₃ CH₂ h1B-2-7-98 H H CH₃ CH₂ h2 B-2-7-99 H H CH₃ CH₂ h3 B-2-7-100 H H CH₃ CH₂ h4B-2-7-101 H H CH₃ CH₂ h5 B-2-7-102 H H CH₃ CH₂ h6 B-2-7-103 H H CH₃ CH₂h7 B-2-7-104 H H CH₃ CH₂ h8 B-2-7-105 H H Cl CH₂ h1 B-2-7-106 H H Cl CH₂h2 B-2-7-107 H H Cl CH₂ h3 B-2-7-108 H H Cl CH₂ h4 B-2-7-109 H H Cl CH₂h5 B-2-7-110 H H Cl CH₂ h6 B-2-7-111 H H Cl CH₂ h7 B-2-7-112 H H Cl CH₂h8 B-2-7-113 H H F CH₂ h1 B-2-7-114 H H F CH₂ h2 B-2-7-115 H H F CH₂ h3B-2-7-116 H H F CH₂ h4 B-2-7-117 H H F CH₂ h5 B-2-7-118 H H F CH₂ h6B-2-7-119 H H F CH₂ h7 B-2-7-120 H H F CH₂ h8

TABLE 18

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₉ R₆R_(1a) R_(1b) D Z index B-2-8-1  H H H H CH₂ h1 & NMR B-2-8-2  H H H HCH₂ h2 B-2-8-3  H H H H CH₂ h3 B-2-8-4  H H H H CH₂ h4 B-2-8-5  H H H HCH₂ h5 B-2-8-6  H H H H CH₂ h6 B-2-8-7  H H H H CH₂ h7 B-2-8-8  H H H HCH₂ h8 B-2-8-9  H H H H CH₂CH₂ h1 B-2-8-10 H H H H CH₂CH₂ h2 B-2-8-11 HH H H CH₂CH₂ h3 B-2-8-12 H H H H CH₂CH₂ h4 B-2-8-13 H H H H CH₂CH₂ h5B-2-8-14 H H H H CH₂CH₂ h6 B-2-8-15 H H H H CH₂CH₂ h7 B-2-8-16 H H H HCH₂CH₂ h8 B-2-8-17 H H H H CH₂CH₂CH₂ h1 B-2-8-18 H H H H CH₂CH₂CH₂ h2B-2-8-19 H H H H CH₂CH₂CH₂ h3 B-2-8-20 H H H H CH₂CH₂CH₂ h4 B-2-8-21 H HH H CH₂CH₂CH₂ h5 B-2-8-22 H H H H CH₂CH₂CH₂ h6 B-2-8-23 H H H HCH₂CH₂CH₂ h7 B-2-8-24 H H H H CH₂CH₂CH₂ h8 B-2-8-25 H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-8-26 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-8-27 HH H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-8-28 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h4B-2-8-29 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-8-30 H H H HCH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-8-31 H H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-8-32 HH H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-8-33 CH3 H H H CH₂ h1 B-2-8-34 CH₃ H H HCH₂ h2 B-2-8-35 CH₃ H H H CH₂ h3 B-2-8-36 CH₃ H H H CH₂ h4 B-2-8-37 CR₃H H H CH₂ h5 B-2-8-38 CH₃ H H H CH₂ h6 B-2-8-39 CH₃ H H H CH₂ h7B-2-8-40 CH₃ H H H CH₂ h8 B-2-8-41 CH₂CH₃ H H H CH₂ h1 & NMR B-2-8-42CH₂CH₃ H H H CH₂ h2 B-2-8-43 CH₂CH₃ H H H CH₂ h3 B-2-8-44 CH₂CH₃ H H HCH₂ h4 B-2-8-45 CH₂CH₃ H H H CH₂ h5 B-2-8-46 CH₂CH₃ H H H CH₂ h6B-2-8-47 CH₂CH₃ H H H CH₂ h7 B-2-8-48 CH₂CH₃ H H H CH₂ h8 B-2-8-49CH₂CH₂CH₃ H H H CH₂ h1 B-2-8-50 CH₂CH₂CH₃ H H H CH₂ h2 B-2-8-51CH₂CH₂CH₃ H H H CH₂ h3 B-2-8-52 CH₂CH₂CH₃ H H H CH₂ h4 B-2-8-53CH₂CH₂CH₃ H H H CH₂ h5 B-2-8-54 CH₂CH₂CH₃ H H H CH₂ h6 B-2-8-55CH₂CH₂CH₃ H H H CH₂ h7 B-2-8-56 CH₂CH₂CH₃ H H H CH₂ h8 B-2-8-57 CH(CH₃)₂H H H CH₂ h1 B-2-8-58 CH(CH₃)₂ H H H CH₂ h2 B-2-8-59 CH(CH₃)₂ H H H CH₂h3 B-2-8-6O CH(CH₃)₂ H H H CH₂ h4 B-2-8-61 CH(CH₃)₂ H H H CH₂ h5B-2-8-62 CH(CH₃)₂ H H H CH₂ h6 B-2-8-63 CH(CH₃)₂ H H H CH₂ h7 B-2-8-64CH(CH₃)₂ H H H CH₂ h8 B-2-8-65 CH₂C₆H₅ H H H CH₂ h1 B-2-8-66 CH₂C₆H₅ H HH CH₂ h2 B-2-8-67 CH₂C₆H₅ H H H CH₂ h3 B-2-8-68 CH₂C₆H₅ H H H CH₂ h4B-2-8-69 CH₂C₆H₅ H H H CH₂ h5 B-2-8-70 CH₂C₆H₅ H H H CH₂ h6 B-2-8-71CH₂C₆H₅ H H H CH₂ h7 B-2-8-72 CH₂C₆H₅ H H H CH₂ h8 B-2-8-73 H CH₃ H HCH₂ h1 [157-159] B-2-8-74 H CH₃ H H CH₂ h2 B-2-8-75 H CH₃ H H CH₂ h3B-2-8-76 H CH₃ H H CH₂ h4 B-2-8-77 H CH₃ H H CH₂ h5 B-2-8-78 H CH₃ H HCH₂ h6 B-2-8-79 H CH₃ H H CH₂ h7 B-2-8-80 H CH₃ H H CH₂ h8 B-2-8-81 H HCH₃ H CH₂ h1 B-2-8-82 H H CH₃ H CH₂ h2 B-2-8-83 H H CH₃ H CH₂ h3B-2-8-84 H H CH₃ H CH₂ h4 B-2-8-85 H H CH₃ H CH₂ h5 B-2-8-86 H H CH₃ HCH₂ h6 B-2-8-87 H H CH₃ H CH₂ h7 B-2-8-88 H H CH₃ H CH₂ h8 B-2-8-89 H HCl H CH₂ h1 B-2-8-90 H H Cl H CH₂ h2 B-2-8-91 H H Cl H CH₂ h3 B-2-8-92 HH Cl H CH₂ h4 B-2-8-93 H H Cl H CH₂ h5 B-2-8-94 H H Cl H CH₂ h6 B-2-8-95H H Cl H CH₂ h7 B-2-8-96 H H Cl H CH₂ h8 B-2-8-97 H H F H CH₂ h1B-2-8-98 H H F H CH₂ h2 B-2-8-99 H H F H CH₂ h3 B-2-8-100 H H F H CH₂ h4B-2-8-101 H H F H CH₂ h5 B-2-8-102 H H F H CH₂ h6 B-2-8-103 H H F H CH₂h7 B-2-8-104 H H F H CH₂ h8 B-2-8-105 H H H CH₃ CH₂ h1 B-2-8-106 H H HCH₃ CH₂ h2 B-2-8-107 H H H CH₃ CH₂ h3 B-2-8-108 H H H CH₃ CH₂ h4B-2-8-109 H H H CH₃ CH₂ h5 B-2-8-110 H H H CH₃ CH₂ h6 B-2-8-111 H H HCH₃ CH₂ h7 B-2-8-112 H H H CH₃ CH₂ h8 B-2-8-113 H H H Cl CH₂ h1B-2-8-114 H H H Cl CH₂ h2 B-2-8-115 H H H Cl CH₂ h3 B-2-8-116 H H H ClCH₂ h4 B-2-8-117 H H H Cl CH₂ h5 B-2-8-118 H H H Cl CH₂ h6 B-2-8-119 H HH Cl CH₂ h7 B-2-8-120 H H H Cl CH₂ h8 B-2-8-121 H H H F CH₂ h1 B-2-8-122H H H F CH₂ h2 B-2-8-123 H H H F CH₂ h3 B-2-8-124 H H H F CH₂ h4B-2-8-125 H H H F CH₂ h5 B-2-8-126 H H H F CH₂ h6 B-2-8-127 H H H F CH₂h7 B-2-8-128 H H H F CH₂ h8

TABLE 19

Physical Constant Compound [ ] m.p. ° C. No. D Z n_(D) refractive indexB-2-9-1  CH₂ h1 [129-131] B-2-9-2  CH₂ h2 B-2-9-3  CH₂ h3 B-2-9-4  CH₂h4 B-2-9-5  CH₂ h5 B-2-9-6  CH₂ h6 B-2-9-7  CH₂ h7 B-2-9-8  CH₂ h8B-2-9-9  CH₂CH₂ h1 B-2-9-10 CH₂CH₂ h2 B-2-9-11 CH₂CH₂ h3 B-2-9-12 CH₂CH₂h4 B-2-9-13 CH₂CH₂ h5 B-2-9-14 CH₂CH₂ h6 B-2-9-15 CH₂CH₂ h7 B-2-9-16CH₂CH₂ h8 B-2-9-17 CH₂CH₂CH₂ h1 B-2-9-18 CH₂CH₂CH₂ h2 B-2-9-19 CH₂CH₂CH₂h3 B-2-9-20 CH₂CH₂CH₂ h4 B-2-9-21 CH₂CH₂CH₂ h5 B-2-9-22 CH₂CH₂CH₂ h6B-2-9-23 CH₂CH₂CH₂ h7 B-2-9-24 CH₂CH₂CH₂ h8 B-2-9-25 CH₂CH₂CH₂CH₂CH₂CH₂h1 B-2-9-26 CH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-9-27 CH₂CH₂CH₂CH₂CH₂CH₂ h3B-2-9-28 CH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-9-29 CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-9-30CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-9-31 CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-9-32CH₂CH₂CH₂CH₂CH₂CH₂ h8

TABLE 20

Physical Constant Compound [ ] m.p. ° C. No. D Z n_(D) refractive indexB-2-10-1  CH₂ h1 B-2-10-2  CH₂ h2 B-2-10-3  CH₂ h3 B-2-10-4  CH₂ h4B-2-10-5  CH₂ h5 B-2-10-6  CH₂ h6 B-2-10-7  CH₂ h7 B-2-10-8  CH₂ h8B-2-10-9  CH₂CH₂ h1 B-2-10-10 CH₂CH₂ h2 B-2-10-11 CH₂CH₂ h3 B-2-10-12CH₂CH₂ h4 B-2-10-13 CH₂CH₂ h5 B-2-10-14 CH₂CH₂ h6 B-2-10-15 CH₂CH₂ h7B-2-10-16 CH₂CH₂ h8 B-2-10-17 CH₂CH₂CH₂ h1 B-2-10-18 CH₂CH₂CH₂ h2B-2-10-19 CH₂CH₂CH₂ h3 B-2-10-20 CH₂CH₂CH₂ h4 B-2-10-21 CH₂CH₂CH₂ h5B-2-10-22 CH₂CH₂CH₂ h6 B-2-10-23 CH₂CH₂CH₂ h7 B-2-10-24 CH₂CH₂CH₂ h8B-2-10-25 CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-10-26 CH₂CH₂CH₂CH₂CH₂CH₂ h2B-2-10-27 CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-10-28 CH₂CH₂CH₂CH₂CH₂CH₂ h4B-2-10-29 CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-10-30 CH₂CH₂CH₂CH₂CH₂CH₂ h6B-2-10-31 CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-10-32 CH₂CH₂CH₂CH₂CH₂CH₂ h8

TABLE 21

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₅ R_(6a)R_(6b) D Z index B-2-11-1  H H H CH₂ h1 [180-184] B-2-11-2  H H H CH₂ h2[126-128] B-2-11-3  H H H CH₂ h3 B-2-11-4  H H H CH₂ h4 B-2-11-5  H H HCH₂ h5 B-2-11-6  H H H CH₂ h6 B-2-11-7  H H H CH₂ h7 B-2-11-8  H H H CH₂h8 B-2-11-9  H H H CH₂CH₂ h1 B-2-11-10 H H H CH₂CH₂ h2 B-2-11-11 H H HCH₂CH₂ h3 B-2-11-12 H H H CH₂CH₂ h4 B-2-11-13 H H H CH₂CH₂ h5 B-2-11-14H H H CH₂CH₂ h6 B-2-11-15 H H H CH₂CH₂ h7 B-2-11-16 H H H CH₂CH₂ h8B-2-11-17 H H H CH₂CH₂CH₂ h1 B-2-11-18 H H H CH₂CH₂CH₂ h2 B-2-11-19 H HH CH₂CH₂CH₂ h3 B-2-11-20 H H H CH₂CH₂CH₂ h4 B-2-11-21 H H H CH₂CH₂CH₂ h5B-2-11-22 H H H CH₂CH₂CH₂ h6 B-2-11-23 H H H CH₂CH₂CH₂ h7 B-2-11-24 H HH CH₂CH₂CH₂ h8 B-2-11-25 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-11-26 H H HCH₂CH₂CH₂CH₂CH₂CH₂ h2 B-2-11-27 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-11-28 HH H CH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-11-29 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5B-2-11-30 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-11-31 H H H CH₂CH₂CH₂CH₂CH₂CH₂h7 B-2-11-32 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-11-33 CH₃ H H CH₂ h1B-2-11-34 CH₃ H H CH₂ h2 B-2-11-35 CH₃ H H CH₂ h3 B-2-11-36 CH₃ H H CH₂h4 B-2-11-37 CH₃ H H CH₂ h5 B-2-11-38 CH₃ H H CH₂ h6 B-2-11-39 CH₃ H HCH₂ h7 B-2-11-40 CH₃ H H CH₂ h8 B-2-11-41 H CH₃ H CH₂ h1 B-2-11-42 H CH₃H CH₂ h2 B-2-11-43 H CH₃ H CH₂ h3 B-2-11-44 H CH₃ H CH₂ h4 B-2-11-45 HCH₃ H CH₂ h5 B-2-11-46 H CH₃ H CH₂ h6 B-2-11-47 H CH₃ H CH₂ h7 B-2-11-48H CH₃ H CH₂ h8 B-2-11-49 H H CH₃ CH₂ h1 B-2-11-50 H H CH₃ CH₂ h2B-2-11-51 H H CH₃ CH₂ h3 B-2-11-52 H H CH₃ CH₂ h4 B-2-11-53 H H CH₃ CH₂h5 B-2-11-54 H H CH₃ CH₂ h6 B-2-11-55 H H CH₃ CH₂ h7 B-2-11-56 H H CH₃CH₂ h8

TABLE 22

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₅ R_(6a)R_(6b) D Z index B-2-12-1  H H H CH₂ h1 B-2-12-2  H H H CH₂ h2 B-2-12-3 H H H CH₂ h3 B-2-12-4  H H H CH₂ h4 B-2-12-5  H H H CH₂ h5 B-2-12-6  H HH CH₂ h6 B-2-12-7  H H H CH₂ h7 B-2-12-8  H H H CH₂ h8 B-2-12-9  H H HCH₂CH₂ h1 B-2-12-10 H H H CH₂CH₂ h2 B-2-12-11 H H H CH₂CH₂ h3 B-2-12-12H H H CH₂CH₂ h4 B-2-12-13 H H H CH₂CH₂ h5 B-2-12-14 H H H CH₂CH₂ h6B-2-12-15 H H H CH₂CH₂ h7 B-2-12-16 H H H CH₂CH₂ h8 B-2-12-17 H H HCH₂CH₂CH₂ h1 B-2-12-18 H H H CH₂CH₂CH₂ h2 B-2-12-19 H H H CH₂CH₂CH₂ h3B-2-12-20 H H H CH₂CH₂CH₂ h4 B-2-12-21 H H H CH₂CH₂CH₂ h5 B-2-12-22 H HH CH₂CH₂CH₂ h6 B-2-12-23 H H H CH₂CH₂CH₂ h7 B-2-12-24 H H H CH₂CH₂CH₂ h8B-2-12-25 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-12-26 H H H CH₂CH₂CH₂CH₂CH₂CH₂h2 B-2-12-27 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-12-28 H H HCH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-12-29 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-12-30 HH H CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-12-31 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7B-2-12-32 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-12-33 CH₃ H H CH₂ h1 B-2-12-34CH₃ H H CH₂ h2 B-2-12-35 CH₃ H H CH₂ h3 B-2-12-36 CH₃ H H CH₂ h4B-2-12-37 CH₃ H H CH₂ h5 B-2-12-38 CH₃ H H CH₂ h6 B-2-12-39 CH₃ H H CH₂h7 B-2-12-40 CH₃ H H CH₂ h8 B-2-12-41 H CH₃ H CH₂ h1 B-2-12-42 H CH₃ HCH₂ h2 B-2-12-43 H CH₃ H CH₂ h3 B-2-12-44 H CH₃ H CH₂ h4 B-2-12-45 H CH₃H CH₂ h5 B-2-12-46 H CH₃ H CH₂ h6 B-2-12-47 H CH₃ H CH₂ h7 B-2-12-48 HCH₃ H CH₂ h8 B-2-12-49 H H CH₃ CH₂ h1 B-2-12-50 H H CH₃ CH₂ h2 B-2-12-51H H CH₃ CH₂ h3 B-2-12-52 H H CH₃ CH₂ h4 B-2-12-53 H H CH₃ CH₂ h5B-2-12-54 H H CH₃ CH₂ h6 B-2-12-55 H H CH₃ CH₂ h7 B-2-12-56 H H CH₃ CH₂h8

TABLE 23

Physical Constant Compound [ ] m.p. ° C. No. D Z n_(D) refractive indexB-2-13-1  CH₂ h1 & NMR B-2-13-2  CH₂ h2 B-2-13-3  CH₂ h3 B-2-13-4  CH₂h4 B-2-13-5  CH₂ h5 B-2-13-6  CH₂ h6 B-2-13-7  CH₂ h7 B-2-13-8  CH₂ h8B-2-13-9  CH₂CH₂ h1 B-2-13-10 CH₂CH₂ h2 B-2-13-11 CH₂CH₂ h3 B-2-13-12CH₂CH₂ h4 B-2-13-13 CH₂CH₂ h5 B-2-13-14 CH₂CH₂ h6 B-2-13-15 CH₂CH₂ h7B-2-13-16 CH₂CH₂ h8 B-2-13-17 CH₂CH₂CH₂ h1 B-2-13-18 CH₂CH₂CH₂ h2B-2-13-19 CH₂CH₂CH₂ h3 B-2-13-20 CH₂CH₂CH₂ h4 B-2-13-21 CH₂CH₂CH₂ h5B-2-13-22 CH₂CH₂CH₂ h6 B-2-13-23 CH₂CH₂CH₂ h7 B-2-13-24 CH₂CH₂CH₂ h8B-2-13-25 CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-13-26 CH₂CH₂CH₂CH₂CH₂CH₂ h2B-2-13-27 CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-13-28 CH₂CH₂CH₂CH₂CH₂CH₂ h4B-2-13-29 CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-13-30 CH₂CH₂CH₂CH₂CH₂CH₂ h6B-2-13-31 CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-13-32 CH₂CH₂CH₂CH₂CH₂CH₂ h8

TABLE 24

Physical Constant Compound [ ] m.p. ° C. No. D Z n_(D) refractive indexB-2-14-1  CH₂ h1 B-2-14-2  CH₂ h2 B-2-14-3  CH₂ h3 B-2-14-4  CH₂ h4B-2-14-5  CH₂ h5 B-2-14-6  CH₂ h6 B-2-14-7  CH₂ h7 B-2-14-8  CH₂ h8B-2-14-9  CH₂CH₂ h1 B-2-14-10 CH₂CH₂ h2 B-2-14-11 CH₂CH₂ h3 B-2-14-12CH₂CH₂ h4 B-2-14-13 CH₂CH₂ h5 B-2-14-14 CH₂CH₂ h6 B-2-14-15 CH₂CH₂ h7B-2-14-16 CH₂CH₂ h8 B-2-14-17 CH₂CH₂CH₂ h1 B-2-14-18 CH₂CH₂CH₂ h2B-2-14-19 CH₂CH₂CH₂ h3 B-2-14-20 CH₂CH₂CH₂ h4 B-2-14-21 CH₂CH₂CH₂ h5B-2-14-22 CH₂CH₂CH₂ h6 B-2-14-23 CH₂CH₂CH₂ h7 B-2-14-24 CH₂CH₂CH₂ h8B-2-14-25 CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-14-26 CH₂CH₂CH₂CH₂CH₂CH₂ h2B-2-14-27 CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-14-28 CH₂CH₂CH₂CH₂CH₂CH₂ h4B-2-14-29 CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-14-30 CH₂CH₂CH₂CH₂CH₂CH₂ h6B-2-14-31 CH₂CH₂CH₂CH₂CH₂CH₂ h7 B-2-14-32 CH₂CH₂CH₂CH₂CH₂CH₂ h8

TABLE 25

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₅ R_(6a)R_(6b) D Z index B-2-15-1  H H H CH₂ h1 B-2-15-2  H H H CH₂ h2 B-2-15-3 H H H CH₂ h3 B-2-i5-4  H H H CH₂ h4 B-2-15-5  H H H CH₂ h5 B-2-15-6  H HH CH₂ h6 B-2-15-7  H H H CH₂ h7 B-2-15-8  H H H CH₂ h8 B-2-15-9  H H HCH₂CH₂ h1 B-2-15-10 H H H CH₂CH₂ h2 B-2-15-11 H H H CH₂CH₂ h3 B-2-15-12H H H CH₂CH₂ h4 B-2-15-13 H H H CH₂CH₂ h5 B-2-15-14 H H H CH₂CH₂ h6B-2-15-15 H H H CH₂CH₂ h7 B-2-15-16 H H H CH₂CH₂ h8 B-2-15-17 H H HCH₂CH₂CH₂ h1 B-2-15-18 H H H CH₂CH₂CH₂ h2 B-2-15-19 H H H CH₂CH₂CH₂ h3B-2-15-20 H H H CH₂CH₂CH₂ h4 B-2-15-21 H H H CH₂CH₂CH₂ h5 B-2-15-22 H HH CH₂CH₂CH₂ h6 B-2-15-23 H H H CH₂CH₂CH₂ h7 B-2-15-24 H H H CH₂CH₂CH₂ h8B-2-15-25 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-15-26 H H H CH₂CH₂CH₂CH₂CH₂CH₂h2 B-2-15-27 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-15-28 H H HCH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-15-29 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-15-30 HH H CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-15-31 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7B-2-15-32 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-15-33 CH₃ H H CH₂ h1 B-2-15-34CH₃ H H CH₂ h2 B-2-15-35 CH₃ H H CH₂ h3 B-2-15-36 CH₃ H H CH₂ h4B-2-15-37 CH₃ H H CH₂ h5 B-2-15-38 CH₃ H H CH₂ h6 B-2-15-39 CH₃ H H CH₂h7 B-2-15-40 CH₃ H H CH₂ h8 B-2-15-41 H CH₃ H CH₂ h1 B-2-15-42 H CH₃ HCH₂ h2 B-2-15-43 H CH₃ H CH₂ h3 B-2-15-44 H CH₃ H CH₂ h4 B-2-15-45 H CH₃H CH₂ h5 B-2-15-46 H CH₃ H CH₂ h6 B-2-15-47 H CH₃ H CH₂ h7 B-2-15-48 HCH₃ H CH₂ h8 B-2-15-49 H H CH₃ CH₂ h1 B-2-15-50 H H CH₃ CH₂ h2 B-2-15-51H H CH₃ CH₂ h3 B-2-15-52 H H CH₃ CH₂ h4 B-2-15-53 H H CH₃ CH₂ h5B-2-15-54 H H CH₃ CH₂ h6 B-2-15-55 H H CH₃ CH₂ h7 B-2-15-56 H H CH₃ CH₂h8

TABLE 26

Physical Constant [ ] m.p. ° C. Compound n_(D) refractive No. R₅ R_(6a)R_(6b) D Z index B-2-16-1  H H H CH₂ h1 B-2-16-2  H H H CH₂ h2 B-2-16-3 H H H CH₂ h3 B-2-16-4  H H H CH₂ h4 B-2-16-5  H H H CH₂ h5 B-2-16-6  H HH CH₂ h6 B-2-16-7  H H H CH₂ h7 B-2-16-8  H H H CH₂ h8 B-2-16-9  H H HCH₂CH₂ h1 B-2-16-10 H H H CH₂CH₂ h2 B-2-16-11 H H H CH₂CH₂ h3 B-2-16-12H H H CH₂CH₂ h4 B-2-16-13 H H H CH₂CH₂ h5 B-2-16-14 H H H CH₂CH₂ h6B-2-16-15 H H H CH₂CH₂ h7 B-2-16-16 H H H CH₂CH₂ h8 B-2-16-17 H H HCH₂CH₂CH₂ h1 B-2-16-18 H H H CH₂CH₂CH₂ h2 B-2-16-19 H H H CH₂CH₂CH₂ h3B-2-16-20 H H H CH₂CH₂CH₂ h4 B-2-16-21 H H H CH₂CH₂CH₂ h5 B-2-16-22 H HH CH₂CH₂CH₂ h6 B-2-16-23 H H H CH₂CH₂CH₂ h7 B-2-16-24 H H H CH₂CH₂CH₂ h8B-2-16-25 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h1 B-2-16-26 H H H CH₂CH₂CH₂CH₂CH₂CH₂h2 B-2-16-27 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h3 B-2-16-28 H H HCH₂CH₂CH₂CH₂CH₂CH₂ h4 B-2-16-29 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h5 B-2-16-30 HH H CH₂CH₂CH₂CH₂CH₂CH₂ h6 B-2-16-31 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h7B-2-16-32 H H H CH₂CH₂CH₂CH₂CH₂CH₂ h8 B-2-16-33 CH₃ H H CH₂ h1 B-2-16-34CH₃ H H CH₂ h2 B-2-16-35 CH₃ H H CH₂ h3 B-2-16-36 CH₃ H H CH₂ h4B-2-16-37 CH₃ H H CH₂ h5 B-2-16-38 CH₃ H H CH₂ h6 B-2-16-39 CH₃ H H CH₂h7 B-2-16-40 CH₃ H H CH₂ h8 B-2-16-41 H CH₃ H CH₂ h1 B-2-16-42 H CH₃ HCH₂ h2 B-2-16-43 H CH₃ H CH₂ h3 B-2-16-44 H CH₃ H CH₂ h4 B-2-l6-45 H CH₃H CH₂ h5 B-2-16-46 H CH₃ H CH₂ h6 B-2-16-47 H CH₃ H CH₂ h7 B-2-16-48 HCH₃ H CH₂ h8 B-2-16-49 H H CH₃ CH₂ h1 B-2-16-50 H H CH₃ CH₂ h2 B-2-16-51H H CH₃ CH₂ h3 B-2-16-52 H H CH₃ CH₂ h4 B-2-16-53 H H CH₃ CH₂ h5B-2-16-54 H H CH₃ CH₂ h6 B-2-16-55 H H CH₃ CH₂ h7 B-2-16-56 H H CH₃ CH₂h8

TABLE 27

Physical Constant Compound No. A R₃ D Z [ ] m.p. ° C. B-3-1  — H CH₂ h1[150-153] B-3-2  — H CH₂ h2 B-3-3  — H CH₂ h3 B-3-4  6-OMe H CH₂ h1B-3-5  6-OMe H CH₂ h2 B-3-6  6-OMe H CH₂ h3 B-3-7  6-(1-imidazolyl) HCH₂ h1 B-3-8  6-(1-imidazolyl) H CH₂ h2 B-3-9  6-(1-imidazolyl) H CH₂ h3B-3-10 — H CO h1 [129-133] B-3-11 — H CO h2 B-3-12 — H CO h3 B-3-136-OMe H CO h1 B-3-14 6-OMe H CO h2 B-3-15 6-OMe H CO h3 B-3-166-(1-imidazolyl) H CO h1 B-3-17 6-(1-imidazolyl) H CO h2 B-3-186-(1-imidazolyl) H CO h3 B-3-19 — Me CH₂ h1 B-3-20 — Me CH₂ h2 B-3-21 —Me CH₂ h3 B-3-22 6-OMe Me CH₂ h1 B-3-23 6-OMe Me CH₂ h2 B-3-24 6-OMe MeCH₂ h3 B-3-25 6-(1-imidazolyl) Me CH₂ h1 B-3-26 6-(1-imidazolyl) Me CH₂h2 B-3-27 6-(1-imidazolyl) Me CH₂ h3 B-3-28 — Me CO h1 B-3-29 — Me CO h2B-3-30 — Me CO h3 B-3-31 6-OMe Me CO h1 B-3-32 6-OMe Me CO h2 B-3-336-OMe Me CO h3 B-3-34 6-(1-imidazolyl) Me CO h1 B-3-35 6-(1-imidazolyl)Me CO h2 B-3-36 6-(1-imidazolyl) Me CO h3 B-3-37 — CH₂Ph CH₂ h1 B-3-38 —CH₂Ph CH₂ h2 B-3-39 — CH₂Ph CH₂ h3 B-3-40 6-OMe CH₂Ph CH₂ h1 B-3-416-OMe CH₂Ph CH₂ h2 B-3-42 6-OMe CH₂Ph CH₂ h3 B-3-43 6-(1-imidazolyl)CH₂Ph CH₂ h1 B-3-44 6-(1-imidazolyl) CH₂Ph CH₂ h2 B-3-456-(1-imidazolyl) CH₂Ph CH₂ h3 B-3-46 — CH₂Ph CO h1 B-3-47 — CH₂Ph CO h2B-3-48 — CH₂Ph CO h3 B-3-49 6-OMe CH₂Ph CO h1 B-3-50 6-OMe CH₂Ph CO h2B-3-51 6-OMe CH₂Ph CO h3 B-3-52 6-(1-imidazolyl) CH₂Ph CO h1 B-3-536-(1-imidazolyl) CH₂Ph CO h2 B-3-54 6-(1-imidazolyl) CH₂Ph CO h3

TABLE 28

Physical Constant Compound No. A R₃ D Z [ ] m.p. ° C. B-3-55 — H CH₂ h1& NMR B-3-56  — H CH₂ h2 B-3-57  — H CH₂ h3 B-3-58  8-OMe H CH₂ h1[176-180] B-3-59  8-OMe H CH₂ h2 B-3-60  8-OMe H CH₂ h3 B-3-61 8-(1-imidazolyl) H CH₂ h1 [206-210] B-3-62  8-(1-imidazolyl) H CH₂ h2B-3-63  8-(1-imidazolyl) H CH₂ h3 B-3-64  — H CO h1 [253-257] B-3-65  —H CO h2 B-3-66  — H CO h3 B-3-67  8-OMe H CO h1 B-3-68  8-OMe H CO h2B-3-69  8-OMe H CO h3 B-3-70  8-(1-imidazolyl) H CO h1 B-3-71 8-(1-imidazolyl) H CO h2 B-3-72  8-(1-imidazolyl) H CO h3 B-3-73  — MeCH₂ h1 [179-183] B-3-74  — Me CH₂ h2 B-3-75  — Me CH₂ h3 B-3-76  8-OMeMe CH₂ h1 B-3-77  8-OMe Me CH₂ h2 B-3-78  8-OMe Me CH₂ h3 B-3-79 8-(1-imidazolyl) Me CH₂ h1 B-3-80  8-(1-imidazolyl) Me CH₂ h2 B-3-81 8-(1-imidazolyl) Me CH₂ h3 B-3-82  — Me CO h1 B-3-83  — Me CO h2 B-3-84 — Me CO h3 B-3-85  8-OMe Me CO h1 B-3-86  8-OMe Me CO h2 B-3-87  8-OMeMe CO h3 B-3-88  8-(1-imidazolyl) Me CO h1 B-3-89  8-(1-imidazolyl) MeCO h2 B-3-90  8-(1-imidazolyl) Me CO h3 B-3-91  — CH₂Ph CH₂ h1 B-3-92  —CH₂Ph CH₂ h2 B-3-93  — CH₂Ph CH₂ h3 B-3-94  8-OMe CH₂Ph CH₂ h1 B-3-95 8-OMe CH₂Ph CH₂ h2 B-3-96  8-OMe CH₂Ph CH₂ h3 B-3-97  8-(1-imidazolyl)CH₂Ph CH₂ h1 B-3-98  8-(1-imidazolyl) CH₂Ph CH₂ h2 B-3-99 8-(1-imidazolyl) CH₂Ph CH₂ h3 B-3-100 — CH₂Ph CO h1 B-3-101 — CH₂Ph COh2 B-3-102 — CH₂Ph CO h3 B-3-103 8-OMe CH₂Ph CO h1 B-3-104 8-OMe CH₂PhCO h2 B-3-105 8-OMe CH₂Ph CO h3 B-3-106 8-(1-imidazolyl) CH₂Ph CO h1B-3-107 8-(1-imidazolyl) CH₂Ph CO h2 B-3-108 8-(1-imidazolyl) CH₂Ph COh3

TABLE 29

Physical Constant Compound No. A R₃ D Z [ ] m.p. ° C. B-3-109 — H CH₂ h1[137-140] B-3-110 — H CH₂ h2 B-3-111 — H CH₂ h3 B-3-112 8-OMe H CH₂ h1B-3-113 8-OMe H CH₂ h2 B-3-114 8-OMe H CH₂ h3 B-3-115 8-(1-imidazolyl) HCH₂ h1 B-3-116 8-(1-imidazolyl) H CH₂ h2 B-3-117 8-(1-imidazolyl) H CH₂h3 B-3-118 — H CO h1 B-3-119 — H CO h2 B-3-120 — H CO h3 B-3-121 8-OMe HCO h1 B-3-122 8-OMe H CO h2 B-3-123 8-OMe H CO h3 B-3-1248-(1-imidazolyl) H CO h1 B-3-125 8-(1-imidazolyl) H CO h2 B-3-1268-(1-imidazolyl) H CO h3 B-3-127 — Me CH₂ h1 B-3-128 — Me CH₂ h2 B-3-129— Me CH₂ h3 B-3-130 8-OMe Me CH₂ h1 B-3-131 8-OMe Me CH₂ h2 B-3-1328-OMe Me CH₂ h3 B-3-133 8-(1-imidazolyl) Me CH₂ h1 B-3-1348-(1-imidazolyl) Me CH₂ h2 B-3-135 8-(1-imidazolyl) Me CH₂ h3 B-3-136 —Me CO h1 B-3-137 — Me CO h2 B-3-138 — Me CO h3 B-3-139 8-OMe Me CO h1B-3-140 8-OMe Me CO h2 B-3-141 8-OMe Me CO h3 B-3-142 8-(1-imidazolyl)Me CO h1 B-3-143 8-(1-imidazolyl) Me CO h2 B-3-144 8-(1-imidazolyl) MeCO h3 B-3-145 — CH₂Ph CH₂ h1 & NMR B-3-146 — CH₂Ph CH₂ h2 B-3-147 —CH₂Ph CH₂ h3 B-3-148 8-OMe CH₂Ph CH₂ h1 B-3-149 8-OMe CH₂Ph CH₂ h2B-3-150 8-OMe CH₂Ph CH₂ h3 B-3-151 8-(1-imidazolyl) CH₂Ph CH₂ h1 B-3-1528-(1-imidazolyl) CH₂Ph CH₂ h2 B-3-153 8-(1-imidazolyl) CH₂Ph CH₂ h3B-3-154 — CH₂Ph CO h1 B-3-155 — CH₂Ph CO h2 B-3-156 — CH₂Ph CO h3B-3-157 8-OMe CH₂Ph CO h1 B-3-158 8-OMe CH₂Ph CO h2 B-3-159 8-OMe CH₂PhCO h3 B-3-160 8-(1-imidazolyl) CH₂Ph CO h1 B-3-161 8-(1-imidazolyl)CH₂Ph CO h2 B-3-162 8-(1-imidazolyl) CH₂Ph CO h3

¹H-NMR data (deuterated chloro solvent, internal standard TMS)

Unit is δ, a numerical value in parenthesis indicates a proton ratio,and symbols are as follows; s: singlet, d: doublet, t: triplet, q:quartet, m: multiplet, br: broad and brs: broad singlet.

Compound B-1-11

1.7 (s, 3H), 2.0 (s, 6H), 2.1 (s, 3H), 2.3 (s, 3H), 2.9 (d, 1H), 3.0-3.4(m, 4H), 3.7 (m, 1H), 3.9 (m, 2H), 4.0 (d, 1H), 4.3 (m, 1H), 6.9 (d,2H), 7.2 (d, 2H), 7.25 (s, 1H), 7.3 (s, 1H), 7.8 (s, 1H)

Compound B-1-13

1.6 (s, 3H), 1.8 (m, 2H), 1.9 (s, 3H), 2.0 (s, 3H), 2.1 (s, 3H), 2.3 (s,3H), 2.5 (m, 2H), 2.7 (m, 1H), 3.0-4.2 (m, 8H), 6.9 (d, 2H), 7.2 (d,2H), 7.25 (s, 1H), 7.3 (s, 1H), 7.7 (s, 1H)

Compound B-1-28

1.4 (s, 3H), 1.92 (s, 3H), 1.97 (s, 3H), 2.0 (s, 3H), 2.3 (s, 3H), 2.6(m, 4H), 2.7 (m, 3H), 3.0 (d, 1H), 3.1 (m, 4H), 6.7 (m, 3H), 7.2 (m,3H), 7.7 (s, 1H)

Compound B-1-37

1.7 (s, 3H), 2.1 (s, 3H), 2.15 (s, 6H), 2.9 (d, 1H), 3.0-3.4 (m, 4H),3.7 (m, 1H), 3.9 (m, 2H), 3.9 (d, 1H), 4.2 (m, 1H), 6.5 (d, 1H), 6.9 (d,2H), 7.55 (d, 1H), 7.6 (d, 2H)

Compound B-1-39

1.6 (s, 3H), 1.7 (m, 2H), 2.0 (s, 3H), 2.1 (s, 3H), 2.15 (s, 3H),2.5-2.6 (m, 2H), 2.7-2.8 (m, 1H), 3.0-4.2 (m, 8H), 6.5 (d, 1H), 6.8 (d,2H), 7.1 (d, 1H), 7.6 (d, 2H)

Compound B-1-148

1.1 (s, 3H), 1.6 (m, 1H), 1.8 (m, 3H), 1.9 (s, 3H), 2.1 (s, 6H), 2.5 (m,4H), 2.7 (m, 2H), 2.9 (m, 2H), 3.5 (m, 4H), 6.5 (s, 1H), 6.6 (m, 2H),7.1 (s, 1H), 7.2 (m, 2H), 7.7 (s, 1H)

Compound B-1-326

1.43 (s, 3H), 2.03 (s, 3H), 2.12 (s, 6H), 2.60 (s, 2H), 2.5-2.8 (m, 4H),2.80 (d, 1H), 3.10 (d, 1H), 3.40 (br, 2H), 3.75 (br, 2H), 4.25 (br, 1H),7.22 (s, 1H), 7.30 (s, 1H), 7.43 (d, 2H), 7.52 (d, 2H), 7.90 (s, 1H)

Compound B-1-332

1.43 (s, 3H), 2.0 (s, 6H), 2.03 (s, 3H), 2.51 (s, 3H), 2.4-2.8 (m, 4H),2.6 (s, 2H), 2.81 (d, 1H), 3.0 (d, 1H), 3.4 (br, 2H), 3.75 (br, 2H),7.22 (s, 1H), 7.30 (s, 1H), 7.43 (d, 2H), 7.52 (d, 2H), 7.90 (s, 1H)

Compound B-2-1-4

1.3 (s, 3H), 1.8 (m, 1H), 2.0 (m, 1H), 2.1 (s, 6H), 2.15 (s, 3H), 2.7(t, 2H), 3.3 (d, 2H), 4.2 (t, 1H), 4.7 (br, 1H), 6.7 (d, 2H), 7.2 (m,4H), 7.7 (s, 1H)

Compound B-2-1-22

1.4 (s, 3H), 1.4-1.8 (m, 10H), 2.0 (s, 3H), 2.05 (s, 3H), 2.1 (s, 3H),2.3 (s, 3H), 2.8 (d, 1H), 3.0 (d, 1H), 3.1 (t, 2H), 3.8 (br, 1H), 6.6(d, 2H), 7.2 (m, 4H), 7.7 (s, 1H)

Compound B-2-2-2

1.3 (s, 3H), 1.8 (m, 1H), 1.9 (m, 1H), 2.0 (s, 3H), 2.1 (s, 3H), 2.2 (s,3H), 2.7 (m, 2H), 3.3 (m, 2H), 4.3 (m, 1H), 6.5-6.7 (m, 3H), 7.1 (s,1H), 7.2 (s, 1H), 7.2 (m, 1H), 7.8 (s, 1H)

Compound B-2-5-7

1.5 (s, 3H), 1.9 (s, 3H), 2.0 (s, 3H), 2.1 (s, 3H), 2.3 (s, 3H), 3.3 (s,2H), 4.0 (br, 1H), 6.4 (d, 1H), 6.7 (d, 2H), 7.5 (d, 2H), 7.55 (d, 1H)

Compound B-2-8-1

1.5 (s, 3H), 2.0 (s, 3H), 2.05 (s, 3H), 2.1 (s, 3H), 2.8 (d, 1H), 3.2(d, 1H), 3.3 (s, 2H), 4.3 (br, 2H), 6.6 (d, 2H), 7.3 (d, 2H), 7.7 (s,2H)

Compound B-2-8-41

1.0 (t, 3h), 1.4 (s, 3H), 2.0 (s, 3H), 2.05 (s, 3H), 2.1 (s, 3H), 2.8(d, 1H), 3.0 (d, 1H), 3.5 (m, 4H), 6.7 (d, 2H), 7.3 (d, 2H), 7.7 (s, 2H)

Compound B-2-13-1

1.6 (s, 3H), 2.0 (s, 3H), 2.0 (s, 3H), 2.1 (s, 3H), 2.5 (br, 2H), 3.0(d, 1H), 3.2 (d, 1H), 3.3 (s, 2H), 7.2 (s, 1H), 7.3 (d, 2H), 7.3 (s,1H), 7.4 (d, 2H), 7.8 (s, 1H)

Compound B-3-55

1.5 (s, 3H), 2.02 (s, 3H), 2.04 (s, 3H), 2.07 (s, 3H), 2.14 (s, 3H),2.7-2.9 (m, 7H), 3.0-3.2 (m, 3H), 3.8 (d, 1H), 3.9 (d, 1H), 7.0 (m, 2H),7.27 (m, 1H), 7.3 (d, 1H), 7.7 (bs, 1H)

Compound B-3-145

1.4 (s, 3H), 1.8 (m, 2H), 2.06 (s, 3H), 2.09 (s, 3H), 2.10 (s, 3H),2.3-2.4 (m, 4H), 2.5-2.8 (m, 2H), 3.0 (m, 3H), 3.5 (m, 1H), 4.0 (d, 1H),4.3 (dd, 1H), 6.3 (d, 1H), 6.6 (m, 1H), 6.9-7.0 (m, 2H), 7.2-7.3 (m, 5H)

[Preparation of Pharmaceutical Preparation]

Pharmaceutical preparations containing the compounds of the presentinvention were prepared by the following process.

Oral agent (Tablets containing 10 mg of active ingredient) Compound ofthe present invention 10 mg Lactose 81.4 mg Cornstarch 20 mgHydroxypropyl cellulose 4 mg Calcium carboxymethyl cellulose 4 mgMagnesium stearate 0.6 mg Total 120 mg

According to the formulation described above, 50 g of the compound ofthe present invention, 407 g of lactose and 100 g of cornstarch wereuniformly mixed using a fluidized bed granulation coating apparatus(manufactured by Okawara Corporation). To the mixture, 200 g of anaqueous 10% hydroxypropyl cellulose solution was sprayed, followed bygranulation. After drying, the resulting granules were passed through a20-mesh sheave and 20 g of calcium carboxymethyl cellulose and 3 g ofmagnesium stearate were added, followed by compressing using a rotarytablet machine (manufactured by Hata Iron Works Co., Ltd.) and Uskimeasuring 7 mm×8.4R to obtain tables each containing 120 mg of an activeingredient.

EXAMPLE 18 In Vitro Lipid Peroxidation Inhibition

An in vitro lipid peroxidation inhibition of the compounds of thepresent invention was evaluated by measuring a lipid peroxidationactivity in a rat brain homogenate according to a process of Malvy, c.,et al., Biochemical and Biophysical Research Communications, 1980, Vol.95, p. 734-737. That is, a rat brain was extracted and a 5-fold amountof an aqueous phosphoric acid buffered saline solution (pH 7.4)(hereinafter abbreviated to PBS) was added to the brain under icecooling, followed by homogenization using a Teflon homogenizer andfurther centrifugation at 10,000 g for 20 minutes to prepare a brainhomogenate as a supernatant. To the brain homogenate thus prepared, 500μM cysteine, 5 μM sulfuric acid monobasic iron and 100 mM KCl wereadded, followed by incubation at 37° C. for 30 minutes. Malondialdehydeproduced by the composition of lipid peroxidation was measured by athiobarbituric acid process. A 50% inhibitory concentration (hereinafterabbreviated to IC₅₀) of the compounds of the present invention wasdetermined from measured values. The results are shown in Table 30. Ithas been found that the compounds of the present invention have an invitro lipid peroxidation inhibition.

TABLE 30 In vitro lipid peroxidation inhibition Compound No. 50%inhibitory concentration (IC₅₀ μM) B-1-1 0.40 B-1-2 0.31 B-1-18 0.25B-1-4 0.42 B-2-1-1 0.35 B-2-2-1 0.47 B-2-5-1 0.42 B-2-5-3 0.21 B-2-5-820.40 B-2-9-1 0.43 B-3-1 0.34 B-3-10 0.50 B-3-58 0.54 R-1 0.23 R-2 0.23

EXAMPLE 19 Tissue Migration Properties

Tissue migration properties of the compounds of the present inventionwere evaluated by measuring an ex vivo lipid peroxidation inhibition. Asolution or suspension prepared by dissolving or suspending each of testcompounds in an aqueous physiological saline solution or a 1% poly oxyethylene hydrogenated castor oil (NIKKOL HCO-60, manufactured by NikkoChemicals Co., Ltd.) physiological saline solution was intraperitoneallyadministered to SD male rats (one group: 3 rats, 6 weeks old) (availablefrom Nippon SLC Co., Ltd.) at a dose of 100 mg/kg. 30 Minutes afteradministration, rats were bled to death by cutting the carotid arteryand then the brain, heart and kidney were extracted. A lipidperoxidation activity of each tissue homogenate was measured by theprocess described in Example 18. An inhibition ratio in each tissue ofthe compounds of the present invention was determined from the amount oflipid peroxidation produced of a control group (physiological salineadministration group) and a test compound administration group. Theresults are shown in Table 31. As is apparent from the results, thecompounds of the present invention have excellent tissue migrationproperties.

TABLE 31 Ex vivo lipid peroxidation inhibition inhibition ratio (%)Compound No. Brain Heart Kidney B-1-1 96 88 95 B-1-2 79 93 89 B-1-18 7788 89 B-1-4 94 88 90 B-2-1-1 96 88 91 B-2-2-1 97 81 86 B-2-5-1 96 88 88B-2-5-3 95 83 91 B-2-5-82 99 86 92 B-2-9-1 95 95 91 B-3-1 98 90 94B-3-10 97 94 90 B-3-58 96 94 91 R-1 68 59 75 R-2 45 57 84

EXAMPLE 20 In Vivo Antioxidative Activity

An in vivo antioxidative activity of the compounds of the presentinvention was evaluated from an abnormal behavior due to administrationof ferrous chloride into spinal subarachnoid cavity of mice as well asan inhibitory effect of a fatality rate according to the processdescribed in J. Med. Chem., 1997, Vol. 40, p. 559-573. Using Slc:ICRmale mice (one group: 3 to 7 mice, 5 weeks old) (available from NipponSLC Co., Ltd.), 5 μl of a 50 mM ferrous chloride physiological salinesolution was administered to the spinal canal through the space betweenthe fifth lumbar vertebrae and the sixth lumbar vertebrae. 20 to 60minutes after administration of ferrous chloride, symptoms were observedand a score after 60 minutes was determined from symptoms shown in Table32. Each of test compounds was dissolved or suspended in a physiologicalsaline solution or a 1% poly oxy ethylene hydrogenated castor oil(NIKKOL HCO-60, manufactured by Nikko Chemicals Co., Ltd.) physiologicalsaline solution and the resulting solution or suspension wasintraperitoneally or orally administered 30 minutes beforeadministration of ferrous chloride. a 50% inhibitory dose (hereinafterabbreviated to ID₅₀) of the compounds of the present invention wasdetermined from the score of a control group (physiological salineadministration group) and the score of a test compound administrationgroup. The results are shown in Table 33. As is apparent from theresults, the compounds of the present invention have an in vivoantioxidation action.

TABLE 32 Score Symptoms 0 Normal 1 Mice frequently bite hypogastrium orhind part end 2 at least one of the following changes is observed (1)mice frequently bite hind part while rolling (2) hypersensitive reactionand attack reaction against external stimulation (3) tremor 3 clonicconvulsion 4 tonic convulsion or hind part paralysis 5 Death

TABLE 33 In vivo antioxidation action 50% inhibitory concentration (ID₅₀mg/kg) Compound No. Intraperitoneal administration Oral administrationB-1-1 4.4 19 B-1-2 27 13 B-1-18 4.7 7.4 B-1-4 6.2 13 B-2-1-1 4.5 11B-2-2-1 12 13 B-2-5-1 16 17 B-2-5-3 6.2 19 B-2-5-82 15 14 B-2-9-1 4.17.4 B-3-1 5.4 14 R-1 >30 >30 R-2 20 53

As a control, compounds (R-1) and (R-2) of the following formulasdescribed in International Publication WO00/006550 were used.

EXAMPLE 21 Retina Migration Properties

Retina migration properties of the compounds of the present inventionwere evaluated. To SD male rats (one group: 3 rats, 6 weeks old), asolution or suspension prepared by dissolving or suspending each of thetest compounds in a 0.1N hydrochloric acid solution or a 1% poly oxyethylene hydrogenated castor oil (NIKKOL HCO-60) solution was orallyadministered. After 30 minutes, both eyes were extracted and the retinawas separated under ice cooling. A 5% homogenate solution of the retinawas prepared in a 0.1M tris-hydrochloric acid buffer (pH 7.4) under icecooling using a polytron homogenizer for a trace amount (NS-310E:manufactured by Nichion Irika Kiki Co., Ltd.) and, after autoxidation at37° C. for one hour, the amount of lipid peroxidation produced wasdetermined by a thiobarbituric acid process (MASUGI et al., vitamin 51,21-29, 1977). A 30% inhibitory dose (ID₃₀) was determined from theinhibition ratio at each dose. The results are shown in Table 34. As isapparent from the results, the compounds of the present invention havean ex vivo retinal lipid peroxidation production inhibitory action andis also excellent in retina migration properties.

TABLE 34 Lipid peroxidation inhibition 30% inhibitory concentration(ID₃₀ mg/kg, Compound No. oral administration.) in ex vivo retina B-1-25.7 B-1-18 12 B-1-4 6.5 B-2-2-1 7.9

EXAMPLE 22 66 kDa Protein Increase Inhibitory Action

An action for inhibition of an increase in 66 kDa protein in the retinaof rats irradiated with ultraviolet light of the compounds of thepresent invention was evaluated. To Wistar male rats (7 to 9 weeks old),a solution or suspension prepared by dissolving or suspending each oftest compounds in a 0.1N hydrochloric acid solution or a 1% poly oxyethylene hydrogenated castor oil (NIKKOL HCO-60) solution was orallyadministered. After 30 minutes, right eye was irradiated with UV-A (12mW/cm²) using a UV spot light source for 30 minutes. Left eye was notirradiated (control). During irradiation with UV-A and 2 hours beforeand after irradiation, rats were bred under an atmosphere where roomlight is screened. 48 hours after irradiation, the retina was separated.In the same manner as in Example 21, a 5% homogenate solution wasprepared. Regarding a change in retinal protein, SDS-polyacrylamideelectrophoresis was carried out according to the process of Lammli(Nature, 277, 680-685, 1970). Using a 4.5% gel (pH 6.8) as aconcentrated gel, a 10% gel (pH 8.8) as a separated gel, the specimenwas migrated in a buffer for migration (25 mM tris, 192 mM glycine 0.1%SDS) at 20 mA constant current (limit 300 V). After migration, thespecimen was fixed by 15% TCA and ethanol:acetic acid:water (25:8:65)and then stained with ethanol:acetic acid:water (9:2:9) containing 0.25%Coomassie Brilliant Blue R-250. Then, the specimen was decolored withethanol:acetic acid:water (25:8:65) and the 66 kDa protein aftermigration was analyzed by a densitograph. The amount of the protein inthe specimen was determined by a Lowry process. The results are shown inTable 35. As is apparent from the results, the compounds of the presentinvention remarkably inhibit an increase in 66 kDa protein.

TABLE 35 66 kDa protein ratio in retina of rats Compound No. irradiatedwith ultraviolet light (right (N = 3) eye: irradiated/left eye:non-irradiated) Normal group 1 Control group 2.51 B-1-18 1.50 (10 mg/kg,p.o.)

EXAMPLE 23 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) InhibitoryAction

A 5-LO inhibitory activity was measured by a partially modified processof a process of Carter et al. (Carter G. W, et al, J. Pharmacol. Exp.Ther.: 256, 929-37, 1991). That is, human peripheral blood mononuclearcells and each of test compounds dissolved in DMSO (final concentration:1%) were preincubated (37° C., 15 minutes) in a Hanks' balanced saltsolution and 30 μM A23187 was further added, followed by incubation (37°C., 30 minutes). The amount of leukotriene B₄ produced as a result ofincubation was determined by enzyme immunoassay and a 50% productioninhibitory concentration (μM) against 5-LO of each test compound wascalculated. The results are shown in Table 36.

A 15-LO inhibitory activity was measured by a partially modified processof a process of Auerbach et al. (Auerbach B. J, et al., Anal. Biochem.:201, 375-80, 1992). That is, 15-LO obtained from reticulocyte of rabbitand each of test compounds dissolved in DMSO (final concentration: 1%)were preincubated (4° C., 15 minutes) in phosphoric acid buffer (pH 7.4)and 256 μM linoleic acid was further added, followed by incubation (4°C., 10 minutes). The amount of 15-HETE produced as a result ofincubation was determined by spectrophotometry (OD_(660 nm)) and 50%production inhibitory concentration (μM) against 15-LO of each testcompound was calculated. The results are shown in Table 36. Compounds(R-3) and (R-4) (edaravone) of the following formulas were used as acontrol drug.

As is apparent from the results, the compounds of the present inventionhave 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) inhibitoryaction.

TABLE 36 Lipoxygenase inhibitory action 50% inhibitory dose (IC₅₀ μM)Compound No. 5-LO 15-LO B-1-18 2.55 1.54 B-1-34 0.162 5.56 B-2-5-1 0.161.40 B-3-1 2.80 1.57 R-3 >10 (34%) 3.26 R-4 >10 (32%) 5.57

EXAMPLE 24 Acute Oral Toxicity

A single dose of each of the compounds of the present invention wasorally administered to male mice. After observing for 7 days, amortality rate was determined. The results are shown in Table 37. Thecompound (R-3) was used as a control drug. As is apparent from theresults, the compounds of the present invention have low acute oraltoxicity.

TABLE 37 Compound No. Mouse acute oral toxicity (LD₅₀ mg/kg)B-1-18 >1000 B-2-5-1 >2000 B-3-1 >300 R-3 <300

1. A compound represented by the formula (1):B-D-Z  (1) [wherein B represents the following formula (B-1):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4):

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, a C₁₋₆ alkoxy group which may besubstituted with G1, a C₁₋₆ alkylsulfonyl group which may be substitutedwith G1, or a halogen atom; R₆ represents a hydrogen atom, a C₁₋₆ alkylgroup which may be substituted with G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, or a benzoyl group which may be substitutedwith G1, or a tetrahydropyranyl group; G1 represents a cyano group, aformyl group, a hydroxyl group, a C₁₋₆ alkoxy group, an amino group, amonomethylamino group, a dimethylamino group or a halogen atom, srepresents 0 or an integer of 1 to 3, t represents 0 or an integer of 1or 2, and R₄(s) or R₅(s) may be the same or different when s or t is 2or more); R₁ represents a halogen atom, a nitro group, a cyano group, ahydroxyl group, a C₁₋₆ alkyl group which may be substituted with G2, aC₁₋₆ alkoxy group which may be substituted with G2, a C₁₋₆ alkylthiogroup which may be substituted with G2, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G2, an amino group (which may be substitutedwith one or two C₁₋₆ alkyl groups), a benzoyl group which may besubstituted with G2, or a benzyl group which may be substituted with G2;R₂ represents a C₁₋₆ alkyl group which may be substituted with G2; G2represents a cyano group, a formyl group, a hydroxyl group, a C₁₋₆alkoxy group, a C₁₋₆ alkoxycarbonyl group, a nitro group, an aminogroup, a monomethylamino group, a dimethylamino group or a halogen atom;m represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when m is 2 or more; o represents an integer of 2; nrepresents 0 or an integer of 1 to 10, and R₂(s) may be the same ordifferent when n is 2 or more; in the formula (B-1), the dotted linerepresents a single bond or a double bond and does not simultaneouslyrepresent a double bond; Y represents a carbon atom or a nitrogen atom,which may have a substituent selected from the group consisting of ahydrogen and a hydroxyl or a multiple bond that satisfies a valence; Erepresents an oxygen atom, a sulfur atom or the

following formula (1a) when Y represents a carbon atom; (wherein R₆₀represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoylgroup (which may be substituted with a nitro group, a halogen atom, ahydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group); R₇ and R₈each independently represents a hydrogen atom, a cyano group, a hydroxylgroup, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆ alkenyloxy group, a C₂₋₆alkynyloxy group, a C₁₋₆ acyloxy group, a C₃₋₆ cycloalkyl group whichmay be substituted with G2, or a phenyl group which may be substitutedwith G2; j and k independently represent 0 or an integer of 1; lrepresents 0 or an integer of 1 to 16; R₇(s) and R₈(s) may be the sameor different when 1 is 2 or more); E represents the formula (1a) when Yrepresents a nitrogen atom; D represents the formula (1a); Z representsa 2,3-dihydrobenzofuran-2-yl group which is substituted with G3, a2,3-dihydrobenzofuran-3-yl group which is substituted with G3; G3represents the formula: NHR₁₀ {wherein R₁₀ represents a hydrogen atom, aC₁₋₆ alkylcarbonyl group, or a benzoyl group (which may be substitutedwith a nitro group, a halogen atom, a hydroxyl group, a C₁₋₆ alkoxygroup, or a C₁₋₆ alkyl group)}; or the formula: OR₁₁ {wherein R₁₁represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoylgroup (which may be substituted with a hydroxyl group, a C₁₋₆ alkoxygroup, a halogen atom, or a C₁₋₆ alkyl group)}] or a pharmaceuticallyacceptable salt thereof.
 2. A compound represented by the formula (1):B-D-Z  (1) [wherein B represents the following formula (B-1):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4):

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, a C₁₋₆ alkoxy group which may besubstituted with G1, a C₁₋₆ alkylsulfonyl group which may be substitutedwith G1, or a halogen atom; R₆ represents a hydrogen atom, a C₁₋₆ alkylgroup which may be substituted with G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, or a benzoyl group which may be substitutedwith G1, or a tetrahydropyranyl group; G1 represents a cyano group, aformyl group, a hydroxyl group, a C₁₋₆ alkoxy group, an amino group, amonomethylamino group, a dimethylamino group or a halogen atom, srepresents 0 or an integer of 1 to 3, t represents 0 or an integer of 1or 2, and R₄(s) or R₅(s) may be the same or different when s or t is 2or more); R₁ represents a halogen atom, a nitro group, a cyano group, ahydroxyl group, a C₁₋₆ alkyl group which may be substituted with G2, aC₁₋₆ alkoxy group which may be substituted with G2, a C₁₋₆ alkylthiogroup which may be substituted with G2, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G2, an amino group (which may be substitutedwith one or two C₁₋₆ alkyl groups), a benzoyl group which may besubstituted with G2, or a benzyl group which may be substituted with G2;R₂ represents a C₁₋₆ alkyl group which may be substituted with G2; G2represents a cyano group, a formyl group, a hydroxyl group, a C₁₋₆alkoxy group, a C₁₋₆ alkoxycarbonyl group, a nitro group, an aminogroup, a monomethylamino group, a dimethylamino group or a halogen atom;m represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when m is 2 or more; o represents an integer of 1 or 2; when ois 1, n represents 0 or an integer of 1 to 8, when o is 2 n represents 0or an integer of 1 to 10, and R₂(s) may be the same or different when nis 2 or more; in the formula (B-1), the dotted line represents a singlebond or a double bond and does not simultaneously represent a doublebond; Y represents a carbon atom or a nitrogen atom, which may have asubstituent selected from the group consisting of a hydrogen and ahydroxyl or a multiple bond that satisfies a valence; E represents anoxygen atom, a sulfur atom or the

following formula (1a) when Y represents a carbon atom; (wherein R₆₀represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoylgroup (which may be substituted with a nitro group, a halogen atom, ahydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group); R₇ and R₈each independently represents a hydrogen atom, a cyano group, a hydroxylgroup, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆ alkenyloxy group, a C₂₋₆alkynyloxy group, a C₁₋₆ acyloxy group, a C₃₋₆ cycloalkyl group whichmay be substituted with G2, or a phenyl group which may be substitutedwith G2; j and k independently represent 0 or an integer of 1; lrepresents 0 or an integer of 1 to 16; R₇(s) and R₈(s) may be the sameor different when 1 is 2 or more); E represents the formula (1a) when Yrepresents a nitrogen atom; D represents the formula (1a); Z representsa chroman-2-yl group which is substituted with G3, a chroman-4-yl groupwhich is substituted with G3; G3 represents the formula: NHR₁₀ {whereinR₁₀ represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoylgroup (which may be substituted with a nitro group, a halogen atom, ahydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group)}; or theformula: OR₁₁ {wherein R₁₁ represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group (which may be substituted with ahydroxyl group, a C₁₋₆ alkoxy group, a halogen atom, or a C₁₋₆ alkylgroup)}] or a pharmaceutically acceptable salt thereof.
 3. A compoundrepresented by the formula (1):B-D-Z  (1) [wherein B represents the following formula (B-1):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4):

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, a C₁₋₆ alkoxy group which may besubstituted with G1, a C₁₋₆ alkylsulfonyl group which may be substitutedwith G1, or a halogen atom; R₆ represents a hydrogen atom, a C₁₋₆ alkylgroup which may be substituted with G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, or a benzoyl group which may be substitutedwith G1, or a tetrahydropyranyl group; G1 represents a cyano group, aformyl group, a hydroxyl group, a C₁₋₆ alkoxy group, an amino group, amonomethylamino group, a dimethylamino group or a halogen atom, srepresents 0 or an integer of 1 to 3, t represents 0 or an integer of 1or 2, and R₄(s) or R₅(s) may be the same or different when s or t is 2or more); R₁ represents a halogen atom, a nitro group, a cyano group, ahydroxyl group, a C₁₋₆ alkyl group which may be substituted with G2, aC₁₋₆ alkoxy group which may be substituted with G2, a C₁₋₆ alkylthiogroup which may be substituted with G2, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G2, an amino group (which may be substitutedwith one or two C₁₋₆ alkyl groups), a benzoyl group which may besubstituted with G2, or a benzyl group which may be substituted with G2;R₂ represents a C₁₋₆ alkyl group which may be substituted with G2; G2represents a cyano group, a formyl group, a hydroxyl group, a C₁₋₆alkoxy group, a C₁₋₆ alkoxycarbonyl group, a nitro group, an aminogroup, a monomethylamino group, a dimethylamino group or a halogen atom;m represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when m is 2 or more; o represents an integer of 1 or 2; when ois 1, n represents 0 or an integer of 1 to 8, when o is 2 n represents 0or an integer of 1 to 10, and R₂(s) may be the same or different when nis 2 or more; in the formula (B-1), the dotted line represents a singlebond or a double bond and does not simultaneously represent a doublebond; Y represents a carbon atom or a nitrogen atom, which may have asubstituent selected from the group consisting of a hydrogen and ahydroxyl or a multiple bond that satisfies a valence; E represents anoxygen atom, a sulfur atom or the

following formula (1a) when Y represents a carbon atom; (wherein R₆₀represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoylgroup (which may be substituted with a nitro group, a halogen atom, ahydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group); R₇ and R₈each independently represents a hydrogen atom, a cyano group, a hydroxylgroup, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆ alkenyloxy group, a C₂₋₆alkynyloxy group, a C₁₋₆ acyloxy group, a C₃₋₆ cycloalkyl group whichmay be substituted with G2, or a phenyl group which may be substitutedwith G2; j and k independently represent 0 or an integer of 1; lrepresents 0 or an integer of 1 to 16; R₇(s) and R₈(s) may be the sameor different when 1 is 2 or more); E represents the formula (1a) when Yrepresents a nitrogen atom; D represents the formula (1a); Z representsa thiochroman-2-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-2-yl group which is substituted with G3, athiochroman-4-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-3-yl group which is substituted with G3, or a1,3-benzoxathiol-2-yl group which is substituted with G3; G3 representsthe formula: NHR₁₀ {wherein R₁₀ represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group (which may be substituted with anitro group, a halogen atom, a hydroxyl group, a C₁₋₆ alkoxy group, or aC₁₋₆ alkyl group)}; or the formula: OR₁₁ {wherein R₁₁ represents ahydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoyl group (which maybe substituted with a hydroxyl group, a C₁₋₆ alkoxy group, a halogenatom, or a C₁₋₆ alkyl group)}] or a pharmaceutically acceptable saltthereof.
 4. A compound represented by the formula (1):B-D-Z  (1) [wherein B represents the following formula (B-1):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4):

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, a C₁₋₆ alkoxy group which may besubstituted with G1, a C₁₋₆ alkylsulfonyl group which may be substitutedwith G1, or a halogen atom; R₆ represents a hydrogen atom, a C₁₋₆ alkylgroup which may be substituted with G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, or a benzoyl group which may be substitutedwith G1, or a tetrahydropyranyl group; G1 represents a cyano group, aformyl group, a hydroxyl group, a C₁₋₆ alkoxy group, an amino group, amonomethylamino group, a dimethylamino group or a halogen atom, srepresents 0 or an integer of 1 to 3, t represents 0 or an integer of 1or 2, and R₄(s) or R₅(s) may be the same or different when s or t is 2or more); R₁ represents a halogen atom, a nitro group, a cyano group, ahydroxyl group, a C₁₋₆ alkyl group which may be substituted with G2, aC₁₋₆ alkoxy group which may be substituted with G2, a C₁₋₆ alkylthiogroup which may be substituted with G2, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G2, an amino group (which may be substitutedwith one or two C₁₋₆ alkyl groups), a benzoyl group which may besubstituted with G2, or a benzyl group which may be substituted with G2;R₂ represents a C₁₋₆ alkyl group which may be substituted with G2; G2represents a cyano group, a formyl group, a hydroxyl group, a C₁₋₆alkoxy group, a C₁₋₆ alkoxycarbonyl group, a nitro group, an aminogroup, a monomethylamino group, a dimethylamino group or a halogen atom;m represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when m is 2 or more; o represents an integer of 1 or 2; when ois 1, n represents 0 or an integer of 1 to 8, when o is 2 n represents 0or an integer of 1 to 10, and R₂(s) may be the same or different when nis 2 or more; in the formula (B-1), the dotted line represents a singlebond or a double bond and does not simultaneously represent a doublebond; Y represents a carbon atom or a nitrogen atom, which may have asubstituent selected from the group consisting of a hydrogen and ahydroxyl or a multiple bond that satisfies a valence; E represents anoxygen atom, a sulfur atom or the

following formula (1a) when Y represents a carbon atom; (wherein R₆₀represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoylgroup (which may be substituted with a nitro group, a halogen atom, ahydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group); R₇ and R₈each independently represents a hydrogen atom, a cyano group, a hydroxylgroup, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆ alkenyloxy group, a C₂₋₆alkynyloxy group, a C₁₋₆ acyloxy group, a C₃₋₆ cycloalkyl group whichmay be substituted with G2, or a phenyl group which may be substitutedwith G2; j and k independently represent 0 or an integer of 1; lrepresents 0 or an integer of 1 to 16; R₇(s) and R₈(s) may be the sameor different when 1 is 2 or more); E represents the formula (1a) when Yrepresents a nitrogen atom; D represents an oxygen atom, a sulfur atom;Z represents a chroman-2-yl group which is substituted with G3, achroman-4-yl group which is substituted with G3, a2,3-dihydrobenzofuran-2-yl group which is substituted with G3, a2,3-dihydrobenzofuran-3-yl group which is substituted with G3, athiochroman-2-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-2-yl group which is substituted with G3, athiochroman-4-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-3-yl group which is substituted with G3, or a1,3-benzoxathiol-2-yl group which is substituted with G3; G3 representsthe formula: NHR₁₀ {wherein R₁₀ represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group (which may be substituted with anitro group, a halogen atom, a hydroxyl group, a C₁₋₆ alkoxy group, or aC₁₋₆ alkyl group)}; or the formula: OR₁₁ [wherein R₁₁ represents ahydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoyl group (which maybe substituted with a hydroxyl group, a C₁₋₆ alkoxy group, a halogenatom, or a C₁₋₆ alkyl group)}] or a pharmaceutically acceptable saltthereof.
 5. A compound represented by the formula (1):B-D-Z  (1) [wherein B represents the following formula (B-2):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4):

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, a C₁₋₆ alkoxy group which may besubstituted with G1, a C₁₋₆ alkylsulfonyl group which may be substitutedwith G1, or a halogen atom; R₆ represents a hydrogen atom, a C₁₋₆ alkylgroup which may be substituted with G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, or a benzoyl group which may be substitutedwith G1, or a tetrahydropyranyl group; G1 represents a cyano group, aformyl group, a hydroxyl group, a C₁₋₆ alkoxy group, an amino group, amonomethylamino group, a dimethylamino group or a halogen atom, srepresents 0 or an integer of 1 to 3, t represents 0 or an integer of 1or 2, and R₄(s) or R₅(s) may be the same or different when s or t is 2or more); R₁ represents a halogen atom, a nitro group, a cyano group, ahydroxyl group, a C₁₋₆ alkyl group which may be substituted with G2, aC₁₋₆ alkoxy group which may be substituted with G2, a C₁₋₆ alkylthiogroup which may be substituted with G2, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G2, an amino group (which may be substitutedwith one or two C₁₋₆ alkyl groups), a benzoyl group which may besubstituted with G2, or a benzyl group which may be substituted with G2;G2 represents a cyano group, a formyl group, a hydroxyl group, a C₁₋₆alkoxy group, a C₁₋₆ alkoxycarbonyl group, a nitro group, an aminogroup, a monomethylamino group, a dimethylamino group or a halogen atom;m represents 0 or an integer of 1 to 4, and R₁(s) may be the same ordifferent when m is 2 or more; D represents an oxygen atom, a sulfuratom or the following formula (1a):

(wherein R₆₀ represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, ora benzoyl group (which may be substituted with a nitro group, a halogenatom, a hydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkyl group); R₇and R₈ each independently represents a hydrogen atom, a cyano group, ahydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆ alkenyloxy group, aC₂₋₆ alkynyloxy group, a C₁₋₆ acyloxy group, a C₃₋₆ cycloalkyl groupwhich may be substituted with G2, or a phenyl group which may besubstituted with G2; j and k independently represent 0 or an integer of1, and j and k represent 0 when B is (B-2); l represents 0 or an integerof 1 to 16; R₇(s) and R₈(s) may be the same or different when 1 is 2 ormore); X represents an oxygen atom, the formula: SOu (wherein urepresents 0 or an integer of 1 or 2) or the formula: N—R₉ (wherein R₉represents a hydrogen atom, a C₁₋₆ alkyl group which may be substitutedwith G2, or a benzyl group which may be substituted with G2); Zrepresents a chroman-2-yl group which is substituted with G3, achroman-4-yl group which is substituted with G3, a2,3-dihydrobenzofuran-2-yl group which is substituted with G3, a2,3-dihydrobenzofuran-3-yl group which is substituted with G3, athiochroman-2-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-2-yl group which is substituted with G3, athiochroman-4-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-3-yl group which is substituted with G3, or a1,3-benzoxathiol-2-yl group which is substituted with G3; G3 representsthe formula: NHR₁₀ {wherein R₁₀ represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group (which may be substituted with anitro group, a halogen atom, a hydroxyl group, a C₁₋₆ alkoxy group, or aC₁₋₆ alkyl group)); or the formula: OR₁₁ {wherein R₁₁ represents ahydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoyl group (which maybe substituted with a hydroxyl group, a C₁₋₆ alkoxy group, a halogenatom, or a C₁₋₆ alkyl group)}] or a pharmaceutically acceptable saltthereof.
 6. A compound represented by the formula (1):B-D-Z  (1) [wherein B represents the following formula (B-3):

A represents an imidazolyl or pyrazolyl group represented by thefollowing formula (A-1), (A-2), (A-3) or (A-4), or may represent ahydrogen atom or R₁:

(wherein R₄ and R₅ each independently represents a C₁₋₆ alkyl groupwhich may be substituted with G1, a C₁₋₆ alkoxy group which may besubstituted with G1, a C₁₋₆ alkylsulfonyl group which may be substitutedwith G1, or a halogen atom; R₆ represents a hydrogen atom, a C₁₋₆ alkylgroup which may be substituted with G1, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G1, or a benzoyl group which may be substitutedwith G1, or a tetrahydropyranyl group; G1 represents a cyano group, aformyl group, a hydroxyl group, a C₁₋₆ alkoxy group, an amino group, amonomethylamino group, a dimethylamino group or a halogen atom, srepresents 0 or an integer of 1 to 3, t represents 0 or an integer of 1or 2, and R₄(s) or R₅(s) may be the same or different when s or t is 2or more); R₁ represents a halogen atom, a nitro group, a cyano group, ahydroxyl group, a C₁₋₆ alkyl group which may be substituted with G2, aC₁₋₆ alkoxy group which may be substituted with G2, a C₁₋₆ alkylthiogroup which may be substituted with G2, a C₁₋₆ alkylcarbonyl group whichmay be substituted with G2, an amino group (which may be substitutedwith one or two C₁₋₆ alkyl groups), a benzoyl group which may besubstituted with G2, or a benzyl group which may be substituted with G2;R₃ represents a hydrogen atom, a C₁₋₆ alkyl group which may besubstituted with G2, a C₁₋₆ alkylcarbonyl group which may be substitutedwith G2, a benzoyl group which may be substituted with G2, or a benzylgroup which may be substituted with G2; G2 represents a cyano group, aformyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₆alkoxycarbonyl group, a nitro group, an amino group, a monomethylaminogroup, a dimethylamino group or a halogen atom; p represents 0 or aninteger of 1 to 4, and R₁(s) may be the same or different when p is 2 ormore; q and r each independently represents an integer of 1

D represents an oxygen atom, a sulfur atom or the following formula(1a): (wherein R₆₀ represents a hydrogen atom, a C₁₋₆ alkylcarbonylgroup, or a benzoyl group (which may be substituted with a nitro group,a halogen atom, a hydroxyl group, a C₁₋₆ alkoxy group, or a C₁₋₆ alkylgroup); R₇ and R₈ each independently represents a hydrogen atom, a cyanogroup, a hydroxyl group, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆alkoxy group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₆alkenyloxy group, a C₂₋₆ alkynyloxy group, a C₁₋₆ acyloxy group, a C₃₋₆cycloalkyl group which may be substituted with G2, or a phenyl groupwhich may be substituted with G2; j and k independently represent 0 oran integer of 1, and j and k represent 0 when B is (B-2); l represents 0or an integer of 1 to 16; R₇(s) and R₈(s) may be the same or differentwhen 1 is 2 or more); Z represents a chroman-2-yl group which issubstituted with G3, a chroman-4-yl group which is substituted with G3,a 2,3-dihydrobenzofuran-2-yl group which is substituted with G3, a2,3-dihydrobenzofuran-3-yl group which is substituted with G3, athiochroman-2-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-2-yl group which is substituted with G3, athiochroman-4-yl group which is substituted with G3, a2,3-dihydrobenzothiophene-3-yl group which is substituted with G3, or a1,3-benzoxathiol-2-yl group which is substituted with G3; G3 representsthe formula: NHR₁₀ {wherein R₁₀ represents a hydrogen atom, a C₁₋₆alkylcarbonyl group, or a benzoyl group (which may be substituted with anitro group, a halogen atom, a hydroxyl group, a C₁₋₆ alkoxy group, or aC₁₋₆ alkyl group)}; or the formula: OR₁₁ {wherein R₁₁ represents ahydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoyl group (which maybe substituted with a hydroxyl group, a C₁₋₆ alkoxy group, a halogenatom, or a C₁₋₆ alkyl group)}] or a pharmaceutically acceptable saltthereof.
 7. The compound according to any one of claims 1 to 6,

wherein Z represents a group represented by the following formula (Z-1),(Z-2), (Z-3), (Z-4) or (Z-5): [wherein * represents an asymmetric carbonatom; X₁ represents an oxygen atom or a sulfur atom; R₁₂ to R₃₂ eachindependently represents a hydrogen atom or a C₁₋₆ alkyl group, and G3represents the formula: NHR₁₀ {wherein R₁₀ represents a hydrogen atom, aC₁₋₆ alkylcarbonyl group, or a benzoyl group (which may be substitutedwith a nitro group, a halogen atom, a hydroxyl group, a C₁₋₆ alkoxygroup, or a C₁₋₆ alkyl group)}; or the formula: OR₁₁ {wherein R₁₁represents a hydrogen atom, a C₁₋₆ alkylcarbonyl group, or a benzoylgroup (which may be substituted with a hydroxyl group, a C₁₋₆ alkoxygroup, a halogen atom, or a C₁₋₆ alkyl group)}] or a pharmaceuticallyacceptable salt thereof.
 8. A pharmaceutical composition comprising, oneor more compounds or pharmaceutically acceptable salts thereof accordingto any one of claims 1 to 7 and an excipient.